WO2017221250A1

WO2017221250A1 - System and method for use in analysis of chiral molecules

Info

Publication number: WO2017221250A1
Application number: PCT/IL2017/050692
Authority: WO
Inventors: Ron Naaman; Nirit KANTOR-URIEL; Eyal Capua; Anup Kumar; David Waldeck
Original assignee: Yeda Research And Development Co. Ltd.; University Of Pittsburgh-Of The Commonwealth System Of Higher Education
Priority date: 2016-06-23
Filing date: 2017-06-21
Publication date: 2017-12-28

Abstract

A system and method are described, for use in determining parameters of chiral molecules. The system comprising: an electrode comprising an adsorption surface, and at least first and second pairs of electrical contacts defining respectively first and second axes of electrical path being substantially perpendicular to between them, wherein said adsorption surface is configured for adsorption of a plurality of molecules to be tested; a field generating unit configured to selectively apply electric field onto said adsorption surface of said electrode; and a control unit comprising at least a power source utility and a voltage detection utility and configured to generate and transmit electrical current through said electrode via said first pair of electrical contact. The control unit further operates the field generating unit to apply selected electric field onto said electrode, and determine data about resulting Hall voltage between said second pair of electrical contacts. The data about resulting Hall voltage being indicative of chirality of said plurality of molecules.

Description

SYSTEM AND METHOD FOR USE IN

ANALYSIS OF CHIRAL MOLECULES

TECHNOLOGICAL FIELD

The present invention relates to a technique for determining and prediction of molecular parameters, and in particular to determining parameters of chiral molecules and determining parameters of interaction between chiral molecules. BACKGROUND

Molecular interactions result in the broad chemical and biological diversity. In particular, many biological processes are the result of molecular interactions, and/or can be described by such molecular interactions. The ability to provide predictions on energy, probability and strength of interactions between certain molecules or molecular structures plays a big role in drug development and general research relating to biological processes.

A majority of molecules participating in biological processes are chiral molecules, i.e. are asymmetric such that a mirror image of the molecule does not overlap with the molecule itself. Examples of chiral molecules include any helix-type molecule, nucleotides, various amino acids and proteins, sugars etc. Such chiral molecules do not have mirror image symmetry, but possess "hand" like symmetry ("cheir" in Greek) of two distinct enantiomers. Despite the energy cost of keeping molecules chiral, this property has prevailed in biological organisms through evolution.

Various techniques are used to determine chirality and type of enantiomers for a given molecule. A typical conventional technique utilizes shift in linear polarization of light passing through a solution including the molecules to be tested. The two different enantiomers interact with light by shifting polarization thereof in different directions and thus can be identified through measurement of light polarization. Conventionally in computerized simulations of molecular interactions, non- covalent interactions between molecules, as are in biological systems, are commonly described by considering electrostatic and polarization forces between the molecules. This is while quantum mechanics properties are typically neglected to simplify calculations, or only used for determining charge distribution and polarization within a molecule. As a result, intermolecular forces, determined by the molecular charge distributions, are typically processed classically by generating force fields. Typically, such forces include ion-ion forces, charge-dipole forces as well as higher multipole forces, induction forces, and dispersion forces. Hydrogen bonds are typically considered as a special class of electrostatic forces, and hydrophobicity is a collective manifestation of these forces which is typically also included.

Various techniques are known for simulating and predicting molecular behavior and interactions using classical analysis of the forces between molecules, for example U.S. Patent No. 8,145,430 describes a computer- implemented method for calculating a value representative of interaction (VRI) of a proposed ligand with a specified receptor. Hydrophobic interactions between one or more ligand atoms and one or more receptor atoms are scored by a method that awards a bonus for the presence of hydrophobic enclosure of one or more ligand atoms by the receptor. Also, charge-charge hydrogen bonds between a ligand and a receptor are scored by setting a default value for a charge- charge hydrogen bond and awarding a bonus above the default value when one or more specialized predetermined charge-charge hydrogen bond criteria is satisfied. Various charge-charge hydrogen bond criteria are used. Zwitterions, charge, solvation, geometry and electrostatic energy are accounted for.

GENERAL DESCRIPTION

As indicated above, chirality and enantio-selectivity in molecular interactions play role in various biological and chemical processes. There is thus a need in the art for a novel technique for determining and utilizing chirality related data, including various parameters about molecules, for providing better predictions of molecular interactions in various environments.

The present invention provides a novel system and technique for determining type of enantiomers of a given chiral molecules as well as generating data indicative of electrical and magnetic properties of the molecule. Additionally, the technique of the invention may also provide for a technique for use in computer implemented molecular simulations, for characterizing molecular interactions. The presented technique relates to varying interactions between chiral molecules and thus taking into account parameters of chiral selectivity as occurs in molecular biologic interactions.

The technique of the invention is based on the inventors' understanding that charge reorganization in a chiral molecule is accompanies by spin polarization. Thus, charge polarization, generally occurring in molecular interaction, may both be used to determine type of enantiomers of a given molecule and in prediction of molecular interactions in accordance with direction/polarity of the produced spin polarization.

To this end, in the system for determining type of enantiomer of a chiral molecule, molecules selected for inspection are dissolved in a solution to be adsorbed on an electrode (working electrode) having at least two pairs of electrical contacts. A first pair of contacts defining a first axis of electrical path is connectable to a power source for providing electrical current between them and through the working electrode, a second pair of electrical contacts are configured to define a second axis of electrical path through the working electrode, being substantially perpendicular to the first path of electrical conductivity. The molecules are adsorbed onto the electrode when certain electrical current is transmitted through the first pair of electrical contacts. In response to variation in electric field applied onto the molecules (e.g. using a gate electrode), the charge distribution within the molecules is reorganized and thus spin polarization is generated through the molecules. The spin polarization acts on the electrode providing local magnetic field and accordingly generating Hall voltage between the second set of electrical contacts. Direction of the Hall voltage is determined by enantiomer type of the molecules such that certain chirality will provide positive voltage (with respect to certain direction along the second axis) and the opposite chirality will provide negative voltage with respect to the same direction along the second axis. The magnitude of the Hall voltage generally depends on electric field strength, the current between the first pair of electric contacts as well as on level of spin polarization in the molecules, which is generated by the electric field applied thereon. This can be used to determine various parameters of the adsorbed molecules. These parameters may be used for generating an appropriate database, fine tuning simulation parameters as well as characterizing molecules in accordance with pre-existing database. Further, the inventors' understanding that charge reorganization generates spin polarization in accordance with chirality of a molecule may be used in computer implemented processes for simulating molecular interactions. Such computerized simulations generally utilize structural data and effective force fields molecules in combination with modeling of statistical behavior to determine scores (typically corresponding to energy or free energy) for interactions between the molecules. According to the present technique, the method comprises providing structural data about at least first and second molecules relevant for the simulated interaction (e.g. obtaining structural data from a corresponding storage utility); providing data about effective fields (force fields) applied on the at least first and second molecules in accordance with various parameters including: distance between the molecules, special ligands of the molecules and environment (e.g. solvent typically buffered electrolyte solution); and providing data about charge polarization resulting from the effective field. The method further comprises determining one or more chiral centers within structure of said first and second molecules based on the structural data of the molecules. Additionally, based on the charge polarization and the location and direction of the chiral centers, the method comprises determining a level of spin polarization at one or more reactive ends/ligands of said first and second molecules; levels of spin polarization at reactive ends of the interacting molecules may then be used to determine a score associated with variation in interaction energy between the molecules. Such variations may affect interaction energy between molecules having the same or opposite handedness. Thus, chirality of the molecules may play a role already in the simulated processes enabling to better understand chiral selectivity in biological systems as well as enhance prediction accuracy for various processes and material interactions.

It should be understood that spin polarization generally affects molecular interactions by enabling formation of an anti- symmetric multi-electron (or multi- molecule) wavefunction. More specifically, according to quantum mechanics and to Pauli Exclusion Principle, only a single electron can occupy certain state. However as electrons have spin of +1/2 (along a selected axis) two electrons having different spins can occupy together a common spatial or momentum state. In this case, if the spin polarization at the interacting end of two molecules are similar (i.e. triplet state) the interaction energy is increased due to effective repulsion between the electrons, if the spin polarization is opposite (i.e. singlet state) the interaction energy is reduced making it more likely to take place. Generally, lower interaction energy relates to stronger bonding between the two systems/molecules.

Thus, According to a broad aspect of the present invention, there is provided a system for use in determining parameters of chiral molecules comprising:

an electrode comprising an adsorption surface, and at least first and second pairs of electrical contacts defining respectively first and second axes of electrical path being substantially perpendicular to between them, wherein said adsorption surface is configured for adsorption of a plurality of molecules to be tested;

a field generating unit configured to selectively apply electric field onto said adsorption surface of said electrode; and

a control unit comprising at least a power source utility and a voltage detection utility and configured to generate and transmit electrical current through said electrode via said first pair of electrical contacts, operate the field generating unit to apply selected electric field onto said electrode, and determine data about resulting Hall voltage between said second pair of electrical contacts; wherein said data about resulting Hall voltage being indicative of chirality of said plurality of molecules.

According to some embodiments, the system may be configured for determining data indicative of a relation between electric field polarization and spin polarization in said chiral molecules.

According to some embodiments, said electrode may be configured as a working electrode. Additionally or alternatively, said electrode may be located within a test chamber configured for holding a buffer solution. The buffer solution may be an electrolyte solution having a predetermined electrical conductivity.

According to some embodiment, said plurality of molecules may be adsorbed onto said adsorption surface forming a monolayer of molecules.

The field generating unit may be configured a gate electrode being located at a predetermined distance from said adsorption surface and being electrically insulated therefrom.

According to some embodiments, said control unit may be configured and operable for operating said field generating unit for applying pulsating fields being periodically turned ON and OFF with predetermined field strengths.

Additionally or alternatively, said control unit may be configured and operable for determining chirality data about the plurality of molecules in accordance with dependence of Hall voltage with respect to strength of electric field applied by the field generating unit.

According to one other broad aspect of the invention, there is provided a method for use in chirality analysis of molecules, the method comprising: adsorbing sample molecules onto a working electrode, applying varying electrical field onto the adsorbed molecules via a gate electrode, and determining Hall voltage on said working electrode, said determined Hall voltage being indicative of chirality of said ample molecules.

According to some embodiments, said adsorbing sample molecules onto said working electrode may comprise providing a monolayer of said sample molecules onto an adsorption surface of said electrode.

The method may further comprise placing said electrode with said adsorbed molecules within an electrically conductive solution.

According to some embodiments, said applying electric field onto said working electrode comprising providing a gate electrode, being located at a predetermined distance from said electrode with adsorbed molecules while being electrically insulated therefrom, and providing selected electrical voltage onto said gate electrode to thereby apply selected electric field onto said sample molecules.

According to yet some embodiments, the method may further comprise determining a dependence between detected Hall voltage and strength and direction of applied electric field to thereby determine data about type of enantiomer of the sample molecules.

According to yet another broad aspect of the invention, the present invention provides a computer implemented method for use in characterizing molecular interactions between first and second molecules, the method comprising:

providing data about structure of said first and second molecules;

providing data about an effective field applied on said first and second molecules in accordance with a distance between said first and second molecules and providing data about charge polarization resulting from said effective electric field, said distance being below a predetermined threshold distance for interaction;

determining a level of spin polarization at one or more interacting groups of said first and second molecules; and

determining an energy variation for interaction in accordance with data about spin polarization at reactive ends of said first and second molecules. According to some embodiments, said providing data about structure of said at least first and second molecules comprises providing data about chirality of said at least first and second molecules.

The method may further comprise determining data about chirality of said at least first and second molecules, said data about chirality comprises determining one or more chiral centers and a direction of chirality of said molecules.

Additionally or alternatively, the method may further comprise determining a helicity vector being indicative of chirality of at least one of said first and second molecules, said helicity vector being indicative of direction of spin transmission path along the corresponding molecule, said helicity vector extending between chirality center and an interacting end of the molecule; said determining level of spin polarization comprises determining a product between said charge polarization and said helicity vector.

According to some embodiments, said determining an energy variation may comprise determining spin correlation data between said at least first and second molecules. In some embodiments, said spin correlation data may be indicative of a product of spin polarization levels for the at least first and second molecules at the corresponding interacting ends thereof.

Thus, the spin correlation between the two electrodes may serve for calculating the spin configuration dependent energy of interaction between the two electrodes.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

Fig. 1 illustrates schematically a system for determining enantiomer type of chiral molecules according to some embodiments of the present invention;

Figs. 2A and 2B exemplify principles of operation of the system according to some embodiments of the invention, Fig. 2A illustrates the measurement system and Fig. 2B illustrates spin polarization; Figs. 3A to 3D show experimental results for measurement of Hall voltage on chiral and achiral molecules by the system of the present invention;

Fig. 4 shows method operation for use in computerized simulation according to some embodiments of the invention;

Figs. 5A to 5D exemplify effects of charge and spin polarization in chiral molecules;

Figs. 6A to 6C show variation in interaction energy as a result of enantioselectivity of chiral molecules; and

Figs. 7A-7D illustrate two molecules having similar chirality (Fig. 7A) and opposite chirality (Fig. 7B) and corresponding energy variations for interaction energy between the two molecules (Fig. 7C) and between two interacting methyl systems (Fig. 7D) for opposite and similar chirality.

DETAILED DESCRIPTION OF EMBODIMENTS

Reference is made to Fig. 1 illustrating schematically a system 100 for use in characterization of chiral molecules. The system generally includes a test chamber 110 configured for holding a solution with the molecules to be inspected and connectable to a control unit 1000. An electrode 120 (working electrode) is located within the test chamber 110 and configured to allow adsorption of the molecules thereon to enable inspection of the molecules. The electrode 120 is configured with at least two pairs of electrical contacts 130a and 130b, and 140a and 140b. Each pair of electrical contacts defines an axis of electrical path through the electrode such that a first electrical path FA defined by the first pair of electrical contacts 130a and 130b is substantially perpendicular to a second axis of electrical path SA defined by the second pair of electrical contacts 140a and 140b. In this connection, the electrode 120 and the electrical contacts thereof are configured to enable measurements of Hall voltage. Additionally, the test chamber 110 may be provided with a gate electrode 150, configured to applying electric field onto the test chamber 110 and the molecules adsorbed on the electrode 120. The gate electrode 150 is generally electrically insulated from the solution and the electrode 120 and connectable to a voltage source for providing selected gate voltage. It should be noted that the solution is typically an electrolyte buffer solution that is generally electrically conducting to some level. Further, electrode 120 is configured as a working electrode, i.e. transmitting certain current while operation.

The control unit 1000 generally includes, or associated with, at least one power supply unit and at least a voltage detector unit. More specifically, as illustrated in Fig. 1, the control unit 1000 may include a current providing power supply unit 1020 configured to provide selected current transmitted between the first pair of electrical contacts 130a and 130b, and a gate voltage unit 1040 configured to provide selected voltage to the gate electrode 150. Additionally, the control unit includes a Hall Voltage (HV) detector 1030 connectable to the second pair of electrical contacts 140a and 140b and configured to determine voltage generated between them. Additionally the control unit 1000 may include, or be connectable to, a chirality detection module 1010 configured and operable for receiving data about current transmitted through the electrode 120, voltage applied on the gate electrode 150 and Hall voltage detected to determine type of enantiomer of the molecules within test chamber 110.

The Hall-type system 100 is based on a long -known phenomenon relating to the effect of magnetic fields and electrical currents that is also used as a standard way to study properties of semiconductors. Briefly, when current is flowing in a substrate, such as electrode 120, between two electrodes and a magnetic field is applied perpendicular to the current flow, the magnetic field induces an electric potential perpendicular both to the current and the magnetic field direction. The system 100 of the present invention is based on the Hall Effect, but instead of applying an external magnetic field, a local magnetic field is induced due to charge redistribution (polarization) in the adsorbed chiral molecules. The essence of the detection method is illustrated in more details in Figs. 2A and 2B showing the Hall-based electrode of the system and a diagram illustrating spin polarization in chiral (or helix) type molecules. Fig. 2A illustrates the test chamber holding solvent, which may be a buffered electrolyte solution, and a monolayer of molecules being adsorbed on the electrode. The electrode (120) itself has four electric contacts assigned S and D (source and drain) and HI and H2 enabling detection of Hall voltage. The gate electrode G is located outside of the chamber, to be insulated from the solution, and configured to provide electric field thereon. Fig. 2B illustrates spin polarization occurring at the molecules in response to variation in charge distribution, or variation in electric field applied thereon. As already known in the art, chiral and helical molecules can act as spin filters allowing passage of electrons with certain spin state while preventing electrons with the opposite spin states to pass through the molecules.

To provide chiral data about the molecules, a monolayer of the test molecules is adsorbed on a surface of the electrode 120. Further, a constant current or voltage is driven between the source (S) and drain (D) electrodes (130a and 130b) through the system, and the Hall voltage is measured between electrodes HI and H2 (140a and 140b) along the direction perpendicular to the current flow. At rest the Hall voltage is typically negligible as no magnetic field is applied on the electrode 120. If a magnetic field is applied perpendicular to the plane defined by the electrodes then a traditional Hall measurement can be performed. In contrast, According to the technique of the present invention, voltage is applied on the gate electrode 150 that is insulated from the solution (e.g. through a glass cover, e.g. ΙΟΟμιη thick). The applied electrical voltage generates an electrostatic field that acts across the molecular film (inner part of an electrical double layer) and induces a charge polarization. In chiral molecules such charge polarization may be accompanied with spin polarization resulting in localized magnetic fields and development of measurable Hall voltage.

Reference is made to Figs. 3A to 3D showing experimental results obtained at various gate potentials for achiral monolayer (11-mercapto-undecanoic acid-NC) and chiral oligopeptides: L- and D-SHCH₂CH₂CO-{ Ala-Aib}₅-COOH (referred to herein as C5-L and C5-D respectively) and the longer L-SHCH₂CH₂CO-{ Ala- Aib} -COOH (C7-L). The L and D refer to the different handedness of the amino acids units building the oligopeptide thereby resulting in different enantiomers of similar composition. Fig. 3A shows measurements of Hall voltage for different gate voltages applied on C5-L and C5-D molecules. As shown in the figure, the Hall voltage values observed with the chiral molecules show a roughly linear dependence on the applied gate voltage. Fig. 3B shows Hall voltage measured for different molecules of same chirality and the achiral type for different gate voltages. As shown, the longer C7-L molecules result in greater response of Hall voltage for similar gate voltage with respect to the shorted C5-L molecules, and further with respect to the achiral molecules. Fig. 3C shows Hall voltage changes over time for gate voltage turned ON (to -10V) and OFF, after 20 seconds and after 80 seconds respectively, for C7-L molecules. And Fig. 3D shows time dependent Hall measurements for different gate voltages of 2V, 4V, 6V, 8V and 10V in different polarities, where the arrows mark turning the gate voltage ON and OFF. As the molecules are chiral, the charge polarization results in spin polarization creating magnetic field the generated Hall voltage. It should be noted that although the intrinsic spin depolarization of the electrode material (in this example GaN electrode was used) occurs on a sub-microsecond time scale, the high capacitance of the system together with the monolayer of the test molecules results in longer decay time (1/RC where R is the resistance and C is the capacitance). After the spin polarization decays, the electrode and the monolayer are still electrostatically charged (as the gate voltage is ON). However, the spin polarization settles and spins are redistributed resulting in no Hall voltage. When the gate voltage is removed, the charge decays and a charge displacement flows through the molecules in the opposite direction. This charge displacement is accompanied by a spin polarization and it generates a magnetic field which generates a Hall voltage but of the opposite sign, since the spin polarization in the device is in the opposite direction. The Hall signal decays, as the spin polarization decays. Similar effects with opposite signal ware observed in D-oligopeptide, indicating injection of opposite spins. For an external voltage of 10V, the Hall signal obtained from C7-L corresponds to a magnetic field of about 50Oersted, or 5mT. It should be noted that the high capacitance of the device broadens the measured signal in time and therefore the actual signal peak may be higher.

As indicated above, the above described system for determining type of chirality of molecules may be used for determining various propertied of molecules, e.g. including size/length, polarity, and additional electrical characteristics, and for generating of a corresponding database or for characterizing molecules in accordance with pre-prepared database. Further such database may also be used for providing parameters for use in computerized simulations and predictions of molecular interactions.

The computational modeling of molecular interactions in general, and especially of biorecognition events and intermolecular interactions is often performed using Newton's equations, via force fields that are generated from quantum mechanical calculations of molecular charge distributions and polarizabilities. Such computerized modeling typically does not predict any chiral selectivity other than in multi-site structures. In this connection, the present technique provides data and a method for improving the conventional computerized simulations via introducing chirality related effects in molecular interactions. Reference is made to Fig. 4 showing a flow chart describing a method for use in computer implemented processes for determining interaction energy/score between molecules. As shown, structural data of at least first and second molecules is provided 4010. The structural data may be provided based on existing data or be determined as part of the computerized method using force-field calculations and/or quantum-based calculations for inter-molecular atomic interactions. Generally the structural data may be provided by an operator, obtained from a storage utility and/or obtained as a result of intermediate calculation/processing stage. In many simulations, the interacting molecules are modeled as being located in aqueous solution and moving about statistically (e.g. by Brownian motion, or in certain potential variation). When the molecules are determined to be in relatively close distance (in accordance with statistical data about molecular motion, e.g. determining time or probability of interaction), sufficient for interaction, an effective field is determined 4020 between the molecules. The effective field is generally determined in accordance with one or more models of the induced dipole moments in the molecules as will be described in more details further below. The method includes determining the charge polarization in the molecules 4030 resulting from the effective field. The charge polarization may typically be determined based on classical mechanic calculations in accordance with Newton's laws of motion. Based on the structural data of the molecules, one or more chiral centers are identified 4040. Typically the chiral centers may be determined by locating one or more atoms representing pin point for mirror-like asymmetry. In some embodiments, the chiral centers may be determined based on an axis or a plane of mirror asymmetry of the molecule. Further, in some embodiments, a vector is determined passing through the center of chirality (or average center if more than one center exists) and the interacting end of the molecule. To simplify matters, the molecule may be modeled as a helical molecule rotating about the determined vector (helicity vector). Such model may simplify the process of determining direction of spin polarization, however the direction of spin polarization may also be determined using given database of molecular structures. Based on the location and direction of chiral centers, or based on the determined helicity vector, and in accordance with the charge polarization, a level of spin polarization is determined 4050. The level of spin polarization is determined indicating data on probability that electrons at the interacting ends of the molecules are of preferred spin with respect to a predetermined axis (e.g. axis of interaction defined by a vector between the interacting molecules). The levels and directions of spin polarization of the two interacting molecules are processed together to determine a score of spin correlation 4060. The spin correlation generally indicates if the two molecules provide singlet or triplet total spin at the interaction region (interacting ends). As known from Pauli Exclusion Principle, electrons may occupy a common spatial and momentum state while being in singlet total spin state. However total spin state of triplet will result in increased repulsion and reduce score (increase energy) for interaction. Based on the spin correlation the total score for interaction is corrected to include spin and chirality data 4070 thus enhancing simulation results.

In this connection the spin correlation score (SCS) may be determined as:

SCS = A^■ 5_X5₂ + B

where A and B are predetermined parameters and Si and S₂ are the spin polarizations levels of the first and second molecules. The spin polarization level may typically be between -½ and +½. However due to the classical statistical nature and the assumption that a plurality of electrons may take part in spin and charge polarization, the spin level may take values between +½ and -½, while not necessarily being limited to the quantum values. Additionally, according to some embodiments, the values of spin polarization levels may also include data about charge polarization and/or magnitude of spin polarization and thus range between S_max and — S_max where

and N is the number of electrons taking part in the charge redistribution/polarization. Further, the spin polarization may be introduced into the model for predetermined distance below orbital overlapping range, i.e. at distanced where orbitals of the different molecules may start overlapping, for example at distances lower than 0.3nm or 0.2nm in accordance with the relevant orbitals for interaction.

While it is well known that electron exchange and charge penetration contribute significantly to intermolecular forces at short range, they are not always described rigorously by the force fields model. In classical electrostatics, two electrons always repel each other because they have the same charge. While this interaction is preserved in quantum mechanics, the indistinguishability of electrons results in an exchange interaction that can act to stabilize the energy of two electrons whose charge distributions share a region of space (or orbital overlap) as long as they have opposite "spins". Thus, one or the keys to differentiate between classical electrostatics and quantum mechanics is the electron spin. Typically, the spin is neglected when considering intermolecular forces, modeling atoms and molecules as Van Der Waals spheres. Further, at large distances, or for non-covalent bonds between molecules the spin is not expected to have a significant effect for closed shell (all the electrons are paired in the molecular orbitals) interacting molecules. However, the charge polarization for chiral molecules is associated with spin polarization and its inclusion can change the magnitude of the interaction strength between chiral molecules in a way that is intrinsically linked to their chirality. This effects thus provides a model for chiral selectivity in interaction between molecules.

Charge and spin polarization is further exemplified in Figs 5A to 5D illustrating helical molecules with indication on electron cloud (probability density) and spin polarization. Fig. 5A shows a helical molecule with no charge polarization, illustrated as a cloud around the molecule; Fig. 5B illustrates charge polarization resulting from induced dipole interaction between molecules at close distance between them; Figs 5C and 5D illustrate two molecules of similar chirality and of opposite chirality respectively and corresponding spin polarization between them. As shown, when the molecules are in close distance between them, electrons of each molecule repel the electrons of the other molecule forming a dipole like charge distribution. The charge distribution oscillates varying between two dipole directions. However, due to chirality of the molecules, electrons with certain spin direction can be conducted through the molecule along one direction better than electrons of the opposite spin, which causes accumulation of spins polarization at different ends/regions of the molecules. If the two molecules are of the same chirality, shown as helical molecules with similar helicity, the interaction end has spin polarization of opposite directions forming a singlet as shown in Fig. 5C. If the two molecules are of opposite chirality, the spin polarization will result in triplet, i.e. electrons of similar spin at both interacting ends, and further repel the molecules from each other, reducing probability of interaction.

Because the spin polarization is generated by the motion of the electronic charge, it is a dynamic phenomenon. Therefore, the spin polarization occurs simultaneously with the charge polarization, but once the flow of charge stops, the spin direction typically randomizes. In typical organic molecules, biomolecules included, the spin randomization time is quite long and may take microseconds, or even longer. However, once the two molecules interact via the exchange interaction, the spins involved in the interaction can be 'locked' relative to each other (aligned anti -parallel to each other as in Fig. 5C) and the spin randomization may be slowed.

The physical argument can be presented more quantitatively by considering the interaction between two hydrogen atoms. To make the connection to chiral molecules, each H-atom may be considered as being attached to a chiral molecule. This is exemplified in Figs. 6A to 6C illustrating interaction between two hydrogen atoms H being parts of larger chiral molecules Ml and M2. Fig. 6A illustrates the molecules and hydrogen atoms; Figs 6B and 6C show interaction energy for anti-parallel spins (SO) and parallel spin (SI) for charge polarization of 0.1 (Fig. 6B) and 0.01 (Fig. 6C). When two chiral molecules approach each other their charge distributions polarize, so that there is an induced-dipole interaction between them. The magnitude of this interaction is very small. However, the charge polarization is accompanied by a spin polarization, in this specific example spin polarization on the hydrogen atoms. For a given spin alignment in the two interacting hydrogen atoms, the electrostatic interaction can be determined by known quantum mechanics calculations. If the spins are counter-aligned (paired to a singlet), the potential energy curve has a well (i.e. a net attractive force) and if the spins are aligned parallel to each other (forming a triplet), the potential energy curve is repulsive. Because the electrostatic interaction depends on the charge squared, using partial charges of O. le and O.Ole for the charge polarization give significantly different interaction energies (as shown by the difference in energy scale for Fig. 6B and 6C). It should be noted that the dipole moment associated with a typical C-H bond generally indicates a partial charge of about O. le. In fact, the order of magnitude that is found from this simple model calculation agrees well with the art and specifically with that found from recent experiments on the wetting of leucinol grafted surfaces by leucinol (C₃H CH(NH₂)CH₂0H) liquid droplets, for which the Gibbs free energy change of the chiral interaction (or chiral discrimination) per molecule was found to be about 0.25 ks at room temperature.

Additional example is illustrates in Figs. 7A-7D. Figs. 7A and 7B illustrate two molecules having similar chirality (RS, Fig. 7A) and opposite chirality (SS, Fig. 7B). The molecules are illustrated for determining interaction energy between two methyl groups on the different chirality molecules. Figs. 7C and 7D show energy variations interaction energy between the two molecules and between two interacting methyl groups ^»CH3. . CH3^» respectively, for opposite chirality (AS) and similar chirality or parallel spins (PS). As shown in Figs. 7C and 7D, the interaction energy changes as a function of the distance between the carbons of the methyl group as well as a due to chirality direction of the molecules. As shown, the interaction energy for the case in which the two molecules have opposite handedness (AS) is greater with respect to the case in which the two molecules have the same handedness (PS). This illustrates that the spin polarization between the two molecules affects interaction energy and may be determined by chirality of the molecules. The calculations show that the interaction PS in Fig. 7C is less repulsive by about 0.5 kcal/mol at 0.26 nm for the case in which the spins are antiparallel-aligned (paired) than in the case in which the two spins are parallel The calculations for the two interacting ^»CH3. . CH3^» systems (Fig. 7D), and the results show again a less repulsive force for the two opposite spins PS. It should be noted that the difference in interaction energy is found to be of similar order of magnitude as the difference found in experiments on wetting of leucinol grafted surfaces by leucinol [C₃H CH(NH₂)CH₂0H] liquid droplets, for which the Gibbs energy change of the chiral interaction (or chiral discrimination) per molecule was found to be about 0.25 kBT at room temperature.

In this connection it should be noted that the spin polarization typically plays a role in close distance interactions where orbitals of the molecules typically overlap. However, such interaction may be covalent or non-covalent, such as hydrogen bonds, pi-pi bonds etc. Thus, the spin polarization model may operate in computer simulation when molecules are modeled to be at distances of 0.3nm or below, or 0.2nm or below.

Further, even for a partial charge of 10% of that of an electron, the binding energy between hydrogen atoms can be larger than the thermal energy (the thermal energy associated with temperature of 37°C is about 0.6kcal/mol). As a plurality of atoms may interact in this way when two chiral macromolecules come into contact, the interaction among the multiple atom-atom contacts can add up to be above the thermal energy, even for small spin/charge polarization.

The above described technique enables prediction of pronounced enantioselectivity in interaction, as molecules of the same chirality will generally have the spin densities on the interacting atoms anti-parallel, leading to attraction. This is while molecules of opposite chirality will have their spin densities aligned parallel to each other, leading to a repulsive interaction. It should be noted that even when the interacting groups are not chiral groups by themselves, chirality of each molecule as a whole takes place is spin polarization due to charge reorganization as described above.

Further, spin polarization may affect interaction in short range, i.e. when the interacting molecules are in contact (or almost contact). This is as spin correlation has effect only when the wave functions of two electrons are at least partially overlapping, and the correction due to spin correlation increased as the overlap increases.

Thus, the technique of the present invention provides for a novel system for determining chirality of molecules as well as a novel technique for use in computerized modeling of molecular interactions. The technique generally includes computer readable code embedded on a transitory or non-transitory computer readable medium and including computer instructions for performing the method. The method comprising: providing molecular structural data for at least first and second molecules (involved in the modeled interactions); determining one or more chiral centers of the molecules; determining effective field between the molecules at selected distances between them; determining corresponding charge polarization generated by the effective field; in accordance with chirality of the molecules and charge polarization, determining level of spin polarization at one or more interacting ends of the molecules; determining spin correlation score affecting interaction energy; and providing data about variation in interaction energy as a result of enantio selectivity of the interaction.

It should be noted that such computerized model may include molecular motion in a solvent utilizing one or more statistical models and may utilize various known algorithms for statistical parameters. Such models may include Monte-Carlo simulation or any other algorithms.

The spin polarization may generally be determined in accordance with a helicity vector. Such helicity vector may be determined as a vector from the center of chirality of the molecule towards the interaction end, while a direction and magnitude of the helicity vector may be determined in accordance with chirality of the center of chirality (R or S/L enantiomers) and in accordance with strength of spin selectivity of the molecule. These parameters may be determined experimentally using the above described system and/or be provided in a database installed in a memory utility for operational use of the computer running the technique.

Claims

CLAIMS:

1. A system for use in determining parameters of chiral molecules comprising: an electrode comprising an adsorption surface, and at least first and second pairs of electrical contacts defining respectively first and second axes of electrical path being substantially perpendicular to between them, wherein said adsorption surface is configured for adsorption of a plurality of molecules to be tested; a field generating unit configured to selectively apply electric field onto said adsorption surface of said electrode; and

2. The system of Claim 1, configured for determining data indicative of a relation between electric field polarization and spin polarization in said chiral molecules.

3. The system of claim 1 or 2, wherein said electrode being located within a test chamber configured for holding a buffer solution.

4. The system of any one of claims 1 to 3, wherein said plurality of molecules being adsorbed onto said adsorption surface forming a monolayer of molecules.

5. The system of any one of claims 1 to 4, wherein said field generating unit is a gate electrode being located at a predetermined distance from said adsorption surface and is electrically insulated therefrom.

6. The system of any one of claims 1 to 5, wherein said control unit being configured and operable for operating said field generating unit for applying pulsating fields being periodically turned ON and OFF with predetermined field strengths.

7. The system of any one of claims 1 to 6, wherein said control unit is configured and operable for determining chirality data about the plurality of molecules in accordance with dependence of Hall voltage with respect to strength of electric field applied by the field generating unit.

8. A method for use in chirality analysis of molecules, the method comprising: adsorbing sample molecules onto a working electrode, applying varying electrical field onto the adsorbed molecules via a gate electrode, and determining Hall voltage on said working electrode, said determined Hall voltage being indicative of chirality of said ample molecules.

9. The method of Claim 8, wherein said adsorbing sample molecules onto said working electrode comprises providing a monolayer of said sample molecules onto an adsorption surface of said electrode.

10. The method of Claim 8 or 9, wherein said method further comprising placing said electrode with said adsorbed molecules within an electrically conductive solution.

11. The method of any one of Claims 8 to 10, wherein said applying electric field onto said working electrode comprising providing a gate electrode, being located at a predetermined distance from said electrode with adsorbed molecules while being electrically insulated therefrom, and providing selected electrical voltage onto said gate electrode to thereby apply selected electric field onto said sample molecules.

12. The method of any one of Claims 8 to 11, further comprising determining a dependence between detected Hall voltage and strength and direction of applied electric field to thereby determine data about type of enantiomer of the sample molecules.

13. A computer implemented method for use in characterizing molecular interactions between first and second molecules, the method comprising:

providing data about structure of said first and second molecules;

determining an energy variation for interaction in accordance with data about spin polarization at reactive ends of said first and second molecules.

14. The method of Claim 13, wherein said providing data about structure of said at least first and second molecules comprises providing data about chirality of said at least first and second molecules.

15. The method of Claim 13 or 14, further comprising determining data about chirality of said at least first and second molecules, said data about chirality comprises determining one or more chiral centers and a direction of chirality of said molecules.

16. The method of any one of Claims 13 to 15, further comprising determining a helicity vector being indicative of chirality of at least one of said first and second molecules, said helicity vector being indicative of direction of spin transmission path along the corresponding molecule, said helicity vector extending between chirality center and an interacting end of the molecule; said determining level of spin polarization comprises determining a product between said charge polarization and said helicity vector.

17. The method of any one of Claims 13 to 16, wherein said determining an energy variation comprises determining spin correlation data between said at least first and second molecules.

18. The method of Claim 17, wherein said spin correlation data being indicative of a product of spin polarization levels for the at least first and second molecules at the corresponding interacting ends thereof.