Abstract:
The formation mechanism of an alanine-based peptide has been studied by all-atom
molecular dynamics simulations with a recently developed all-atom point-charge force field and the
Generalize Born continuum solvent model at an effective salt concentration of 0.2M. Thirty-two
simulations were conducted. Each simulation was performed for 100 ns. A surprisingly complex
folding process was observed. The development of the helical content can be divided into three
phases with time constants of 0.06 – 0.08, 1.4 –2.3, and 12–13 ns, respectively. Helices initiate
extreme rapidly in the first phase similar to that estimated from explicit solvent simulations.
Hydrophobic collapse also takes place in this phase. A folding intermediate state develops in the
second phase and is unfolded to allow the peptide to reach the transition state in the third phase.
The folding intermediate states are characterized by the two-turn short helices and the transition
states are helix–turn– helix motifs— both of which are stabilized by hydrophobic clusters. The
equilibrium helical content, calculated by both the main-chain ⌽–⌿ torsion angles and the
main-chain hydrogen bonds, is 64 – 66%, which is in remarkable agreement with experiments. After
corrected for the solvent viscosity effect, an extrapolated folding time of 16 –20 ns is obtained that
is in qualitative agreement with experiments. Contrary to the prevailing opinion, neither initiation
nor growth of the helix is the rate-limiting step. Instead, the rate-limiting step for this peptide is
breaking the non-native hydrophobic clusters in order to reach the transition state. The implication
to the folding mechanisms of proteins is also discussed