Energetic approach to the folding of four α-helices connected sequentially

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Abstract
The packing of four α-helices, which each consist of 12 Ala residues and are sequentially connected to each other by a segment of 10 Ala residues, has been investigated by means of energy minimizations. For the lowest energy structure thus obtained, the following features have been found: (i) the four α-helices are intimately packed to form an assembly with an approximately square section; (ii) the distances of closest approach between two adjacent interhelix axes are 7.7±0.2 Å and those between two diagonal interhelix axes are 11.2±0.2 Å; (iii) the adjacent interhelix angles are -163±2°; and (iv) the diagonal interhelix angles are 24±4°. These results indicate that the polypeptide chain, driven by energetics (nonbonded and electrostatic interactions), is folded into a typical left-handed twisted four-helix bundle with an ˜4-fold symmetric array, as observed in most four α-helix proteins. Furthermore, it has been found that the interaction between the loops formed by the connecting segments and the other part of molecule plays a significant role in stabilizing such a bundle structure. The technology developed here and the relevant knowledge obtained through this study are very useful for the study of modeling four-helix bundle proteins.