Accelerated Construction of Kinetic Network Model of Biomolecules Using Steered Molecular Dynamics

A new class of rare event acceleration techniques based on steered molecular dynamics (SMD) simulations is introduced. A stretching force applied on a biomolecule causes it to access large end-to-end distances. Under these conditions the biomolecule undergoes rapid conformational changes that are rare at zero-force conditions. A theory describing kinetics of a biomolecule at various stretching forces is presented. Using the theory, a master-Markov state model (master-MSM) is constructed from rates frequently accessed over a small range of force conditions. The master-MSM is shown to be applicable over a wide range of force conditions. We demonstrate application of the theory to three different biomolecular systems, namely, deca-alanine, TBA (thrombin binding aptamer), and a RNA hairpin. The master-MSM is used to estimate the kinetics at zero-force conditions, i.e., on the unbiased free-energy landscape, resulting inasmuch as 2-6 orders-of-magnitude speed-up over standard molecular dynamics.