Overcoming Sampling Issues and Improving Computational Efficiency in Collective-Variable-Based Enhanced-Sampling Simulations: A Tutorial

This tutorial is designed to help users overcome sampling challenges and improve computational efficiency in collective-variable (CV)-based enhanced-sampling, or importance-sampling, simulations. Toward this end, we introduce well-tempered metadynamics-extended adaptive biasing force (WTM-eABF) and its integration with Gaussian accelerated molecular dynamics (GaMD). Additionally, use will be made of a method for identifying the least-free-energy pathway (LFEP) and multiple concurrent pathways on high-dimensional free-energy surfaces. We illustrate these sampling techniques with the conformational equilibria of trialanine and chignolin in aqueous solution as test cases. This tutorial assumes that the user has prior experience with molecular dynamics (MD) simulations, in general, with the popular program NAMD, and to some extent with Colvars, the module for CV-based calculations. This tutorial can, however, in large measure be used in conjunction with alternate MD engines that support the Colvars module such as GROMACS, LAMMPS, and Tinker-HP.