KINETIC STEPS FOR ALPHA-HELIX FORMATION

The kinetics of alpha-helix formation in polyalanine and polyglycine e icosamers (20-mers) were examined using torsional-coordinate molecular dynamics (MD), Of one hundred fifty-five MD experiments on extended ( Ala)(20) carried out for 0.5 ns each, 129 (83%) formed a persistent al pha-helix. In contrast, the extended state of (Gly)(20) only formed a right-handed alpha-helix in two of the 20 MD experiments (10%), and th ese helices were not as long or as persistent as those of polyalanine, These simulations show helix formation to be a competition between th e rates of (a) forming local hydrogen bonds (i.e. hydrogen bonds betwe en any residue i and its i + 2, i + 3, i + 4, or i + 5th neighbor) and (b) forming nonlocal hydrogen bonds (HBs) between residues widely sep arated in sequence. Local HBs grow rapidly into an alpha-helix; but no nlocal HBs usually retard helix formation by ''trapping'' the polymer in irregular, ''balled-up'' structures. Most trajectories formed some nonlocal HBs, sometimes as many as eight. But, for (Ala)(20), most of these eventually rearranged to form local HBs that lead to alpha-helic es. A simple kinetic model describes the rate of converting nonlocal H Bs into alpha-helices, Torsional-coordinate MD speeds folding by elimi nating bond and angle degrees of freedom and reducing dynamical fricti on. Thus, the observed 210 ps half-life for helix formation is Likely to be a lower bound on the real rate. However, we believe the sequenti al steps observed here mirror those of real systems. Proteins 33:343-3 57, 1998. (C) 1998 Wiley-Liss, Inc.