GB2288601A

GB2288601A - Intra-molecular cross-linking of helical polypeptide chains

Info

Publication number: GB2288601A
Application number: GB9407199A
Authority: GB
Inventors: Peter James Wallace Midgley
Original assignee: Individual
Current assignee: Individual
Priority date: 1994-04-12
Filing date: 1994-04-12
Publication date: 1995-10-25
Also published as: GB9407199D0

Abstract

A polymeric molecule in the form of a helix in which turns of the helix are linked to one another through chemical linkages. The polymer may take the form of a polypeptide chain which has spontaneously formed into an alpha -helix. The helix is then stabilised by linking turns of the helix to one another by reacting together the side chains of the amino acids in the polypeptide chain. Depending on the amino acids used these linkages may be esters, disulphide bridges, am ides, others, acid anhydrides or ionic linkages. Synthesis of novel amino acids with two side chains could allow an amino acid to be linked to the turns of the helix both above and below it.

Description

A POLYMERIC MOLECULE This invention relates to the field of polymer science.

All synthetic and natural polymers consist of small monomer molecules joined together to form long chains. In the vast majority of cases, although not always, each individual molecule is flexible, has no intrinsic rigidity and therefore has no compressive strength, only good tensile strength. In order to form useful materials such chains may be attached to one another through strong covalent chemical bonds (crosslinks) or they may be only relatively loosely held together by weak forces of attraction. Non-crosslinked polymers make excellent fibres which need good tensile strength. Solid polymeric materials can be made from crosslinked or non-crosslinked chains. The compressive strength of solid polymer substances depends upon the degree of cross-linking, and/or the degree to which the chains are packed together. Nevertheless, the polymer chains themselves remain essentially flexible.

The present invention provides a novel way of making a polymeric molecule which is both straight and rigid. Each molecule therefore has compressive strength as well as tensile strength. Crosslinking of such molecules could allow production of a solid polymeric substance which is strong, and has extremely low density. The invention is a polymer in the form of a helical molecule in which turns of the helix are linked to one another by chemical means. The helical structure is thus stabilised in a straight, rigid form.

A specific example of such a polymer molecule is now described in which the helical structure is formed from a polypeptide chain (a chain of amino acids), Crosslinking between the turns of the helix is carried out by reacting together chemically the side chains of appropriate amino acids.

Figure 1 shows an amino acid Figure 2 shows how amino acids are linked in a polymer chain.

Figure 3 illustrates an a-helix and shows a pattern of crosslinks which can be made between adjacent turns of the helix.

Figure 4 shows examples of linkages which can be used to crosslink the turns of the a-helix, using the side chains of known amino acids.

Figure 5 shows one specific example of a cross-linked polymer which can be formed from known amino acids.

In Fig. 1 an amino acid is shown. The central carbon atom 1 has attached to it an amine group 2, a carboxylic acid group 3, a hydrogen atom 4, and a side chain 5 represented by the letter R. The side chain varies depending on the particular amino acid. A polypeptide chain is made by lining the amino group of one amino acid to the acid group of another in sequence until a chain is formed. This is illustrated in Fig.

2. Such chains exist naturally in all biological organisms and can be produced synthetically by well known processes. The sequence of amino acids in the chain can be fully controlled.

A polypeptide chain will, in solution, spontaneously coil into what is known as an helix. This form of the chain is illustrated in Fig. 3. For the sake of clarity, only the central carbon atom 1 of each amino acid is shown. The rest of the polypeptide chain is represented by the line 7. Fig.3 also shows, in the form of dotted lines, the positions of crosslinks 6 which can be made between the amino acids, using their side chains.

Figure 4 describes some possible crosslinking reactions, which can be carried out between the side chains of known amino acids. In the first reaction the side chain of an aspartic acid 8 is linked to that of a serine 9 under acidic conditions to produce an ester crosslinkage 12. In the second reaction a glutamic acid 10 is linked to a serine 9 under acid conditions to form ester linkage 13. In the third reaction the side chains of two cysteine amino acids are linked together under oxidising conditions to form a disulphide bridge. Any or all of these can be used to form crosslinks between adjacent turns of the helix. Other reactions between known amino acid side chains are also be possible including acid anhydride formation between two acid side chains, ether formation between two alcohol side chains, and amide formation between an acid and an amine side chain. Two acid side chains can also be linked through an ionic linkage using eg. a calcium ion. These reactions can be carried out under standard conditions.

Fig.5 shows a very specific example of a possible repeating sequence of six amino acids, linked together in the manner so far described. This Figure shows the need to use a combination of D-amino acids 8, and L-amino acids 9. When D-amino acids are incorporated into the a-helix the side chains point downwards, whereas when L-amino acids are used the side chains point upwards. By combining D- and L-amino acids in a sequence such as that shown in Fig.5 the side chain of one D-amino acid points down towards the side chain of an L-amino acid pointing upwards. The two side chains, are then able to react with one another by the reactions shown in Fig.4 This is one example of many possible amino acid sequences which can be used.

Synthesis of novel amino acids could pro -ide alternative approaches to crosslinking. For example, amino acids could be synthesised in which the hydrogen atom 4 (see Fig 1) is replaced by a side chain. This would allow the amino acid to link to amino acids in turns of the helix both above and below it.

Novel amino acids could also be synthesised with side chains of different lengths, and with different reactive groups than those found naturally. This would allow variation in the length of the crosslink between turns of the helix , as well as allowing different types of chemical linkages to be made.

Both these factors could alter the properties of the molecule, and hence those of the resulting polymer.

Claims

1 A polymer in the form of a helical molecule in which turns of the helix are linked to one another by chemical means.

2 A helical molecule as claimed in claim 1 in which the polymer is a polypeptide chain (i.e. a chain of amino acids).

3 A helical molecule as claimed in claim 2 in which the polypeptide chain forms spontaneously into a naturally occurring helix known as the a-helix.

4 A helical molecule as claimed in claim 2 or claim 3 in which turns of the helix are linked together chemically through the side chains of the amino acids from which the polymer is made.

5 A helical molecule as claimed in any preceding claim which uses novel amino acids to allow a greater degree of crosslinking, different types of chemical linkage, or different lengths of crosslink.