Energetic approach to the folding of four {alpha}-helices connected sequentially

The packing of four -helices, which each consist of 12 Ala residuesand are sequentially connected to each other by a segment of10 Ala residues, has been investigated by means of energy minimizations.For the lowest energy structure thus obtained, the followingfeatures have been found: (i) the four -helices are intimatelypacked to form an assembly with an approximately square section;(ii) the distances of closest approach between two adjacentinterhelix axes are 7.7±0.2 Å and those betweentwo 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 resultsindicate that the polypeptide chain, driven by energetics (nonbondedand electrostatic interactions), is folded into a typical left-handedtwisted four-helix bundle with an {small tilde}4-fold symmetricarray, as observed in most four -helix proteins. Furthermore,it has been found that the interaction between the loops formedby the connecting segments and the other part of molecule playsa significant role in stabilizing such a bundle structure. Thetechnology developed here and the relevant knowledge obtainedthrough this study are very useful for the study of modelingfour-helix bundle proteins.