Unbiased Folding of Helices Using Temperature-Accelerated Molecular Dynamics

We discuss the use of temperature-accelerated MD (TAMD) to enhance the rate at which initially random poly(alanine) coils adopt stable, complete α-helical conformations in all-atom, explicit-solvent MD simulation.  In TAMD, one augments a standard MD simulation with additional variables that tether to collective variables in the MD system, and these auxiliary variables evolve at high temperature and high friction in lockstep with the atomic variables, thereby inducing the collective variables to quickly explore their inherent free energy landscape.  Here, we tether to all backbone φ/ψ angles and accelerate their respective auxiliary variables at fictitious thermal energies between 1 and 6 kcal/mol.  The shortest folding times for Ala₁₇  of < 20 ns are observed at about 2 kcal/mol, and above 3 kcal/mol single α-helices are only short-lived (mean lifetimes < 20 ns).  At 6 kcal/mol, helical states are never observed.  We find that even standard MD simulations can occasionally fold Ala₁₇, but require 100's of ns to do so.   These findings suggest that TAMD may be an appropriate method for accelerated conformational search in protein folding calculations.