We introduced a conformational sampling method in an earlier report: The multi-dimensional virtual-system coupled molecular dynamics (mD-VcMD) enhances conformational sampling of a biomolecular system by computer simulations. Herein, new sampling method, a subzone-based mD-VcMD, is presented as an extension of mD-VcMD. Then, the subzone-based method is extended further using a genetic algorithm (GA) named the GA-guided mD-VcMD. In these methods, iterative simulation runs are performed to increase the sampled region gradually. The new methods have the following benefits: (1) They are free from a production run: i.e., all snapshots from all iterations are useful for analyses. (2) They are free from fine tuning of a weight function (probability distribution function or potential of mean force). (3) A canonical ensemble (i.e., a thermally equilibrated ensemble) is generated from a simple procedure. A thermodynamic weight is assigned to each snapshot. (4) Selective sampling can be performed for particularly addressing a poorly sampled region without breaking the proportion of the canonical ensemble if the poorly sampled conformational region emerges in sampling. By applying the methods to a simple system that involves an energy barrier between potential-energy minima, we demonstrated that the new methods have considerably higher sampling efficiency than the original mD-VcMD does.
Keywords: Canonical ensemble; Computer simulation; Conformational sampling; Enhanced sampling; Generalized ensemble.
2020 THE BIOPHYSICAL SOCIETY OF JAPAN.