LONG TIMESTEP DYNAMICS OF PEPTIDES BY THE DYNAMICS DRIVER APPROACH

Previous experience with the Langevin/implicit-Euler scheme for dynami cs (''LI'') on model systems (butane, water) has shown that LI is nume rically stable for timesteps in the 5-20 fs range but quenches high-fr equency modes. To explore applications to polypeptides, we apply LI to model systems (several dipeptides, a tetrapeptide, and a 13-residue o ligoalanine) and also develop a new dynamics driver approach (''DA''). The DA scheme, based on LI, addresses the important issue of proper s ampling, which is unlikely to be solved by small-timestep integration methods or implicit methods with intrinsic damping at room temperature , such as LI. Equilibrium averages, time-dependent molecular propertie s, and sampling trends at room temperature are reported for both LI an d DA dynamics simulations, which are then compared to those generated by a standard explicit discretization of the Langevin equation with a 1 fs timestep. We find that LI's quenching effects are severe on both the fast and slow (due to vibrational coupling) frequency modes of all -atom polypeptides and lead to more restricted dynamics at moderate ti mesteps (40 fs). The DA approach empirically counteracts these damping effects by adding random atomic perturbations to the coordinates at e ach step (before the minimization of a dynamics function). By restrict ing the energetic fluctuations and controlling the kinetic energy, we are able with a 60 fs timestep to generate continuous trajectories tha t sample more of the relevant conformational space and also reproduce reasonably Boltrmann statistics. Although the timescale for transition may be accelerated by the DA approach, the transitional information o btained for the alanine dipeptide and the tetrapeptide is consistent w ith that obtained by several other theoretical approaches that focus s pecifically on the determination of pathways. While the trajectory for oligoalanine by the explicit scheme over the nanosecond timeframe rem ains in the vicinity of the full alpha(R)-helix starting structure, an d a high-temperature (600 degrees K) MD trajectory departs slowly from the or helical structure, the DA-generated trajectory for the same CP U time exhibits unfolding and refolding and reveals a range of conform ations with an intermediate helix content. Significantly, this range o f states is more consistent with spectroscopic experiments on small pe ptides, as well as the cooperative two-state model for helix-coil tran sition. The good, near-Boltzmann statistics reported for the smaller s ystems above, in combination with the interesting oligoalanine results , suggest that DA is a promising tool for efficiently exploring confor mational spaces of biomolecules and exploring folding/unfolding proces ses of polypeptides. (C) 1995 Wiley-Liss, Inc.