(702f) 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.