Effective Conformational Sampling in Explicit Solvent with Gaussian Biased Accelerated Molecular Dynamics.

In this Article, a user-friendly Gaussian biased accelerated molecular dynamics (GbAMD) method is presented that uses a sum of Gaussians of potential energies as the biased force to accelerate the conformational sampling. The easy parameter setting of GbAMD is demonstrated in a variety of simulation tests for the conformational transitions of proteins with various complexity including the folding of Trpcage, GB1p, and HP35 peptides as well as the functional conformational changes of nCaM and HIV-1 PR proteins. Additionally, the ability of GbAMD in conformational sampling and free-energy evaluation is quantitatively assessed through the comparison of GbAMD simulations on the folding of α-helical Trpcage and β-hairpin GB1p with the accompanying standard dual boost AMD and conventional MD (cMD) simulations. While GbAMD can fold both peptides into their native structures repeatedly in individual trajectories, AMD can only fold Trpcage and cMD fails the folding in both cases. As a result, only GbAMD can quantitatively measure the properties of the equilibrium conformational ensemble of protein folding consistent with experimental data. Also notable is that the structural properties of the indispensable unfolded and transition states in the folding pathways of Trpcage and GB1p characterized by GbAMD simulations are in great agreement with previous simulations on the two peptides. In summary, GbAMD has an effective conformational sampling ability that provides a convenient and effective access for simulating the structural dynamics of biomolecular systems.