Kinetic steps for α-helix formation

The kinetics of α-helix formation in polyalanine and polyglycine eicosamers (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 α-helix. In contrast, the extended state of (Gly)₂₀ only formed a right-handed α- helix in two of the 20 MD experiments (10%), and these helices were not as long or as persistent as those of polyalanine. These simulations show helix formation to be a competition between the rates of (a) forming local hydrogen bonds (i.e. hydrogen bonds between 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 separated in sequence. Local HBs grow rapidly into an α- helix; but nonlocal 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 α-helices. A simple kinetic model describes the rate of converting nonlocal HBs into α-helices. Torsional-coordinate MD speeds folding by eliminating bond and angle degrees of freedom and reducing dynamical friction. 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 sequential steps observed here mirror those of real systems.