Understanding the interaction of ligands with biomolecules is an integral component of drug discovery and development. Challenges for computing thermodynamic and kinetic quantities for pharmaceutically relevant receptor-ligand systems include the size and flexibility of the ligands, large-scale conformational rearrangements of the receptor, accurate force field parameters, simulation efficiency, and sufficient sampling associated with rare events. Our recently developed multiscale milestoning simulation approach, SEEKR (Simulation Enabled Estimation of Kinetic Rates), has demonstrated success in predicting binding (k_on) and unbinding (k_off) kinetics by using molecular dynamics (MD) simulations in regions closer to the binding site and Brownian dynamics (BD) far from the binding site. The MD region is further subdivided into smaller Voronoi tessellations to improve simulation efficiency and parallelization. Currently, all MD simulations are run using general molecular mechanics (MM) forcefields. Calculation accuracy can be further improved by using quantum mechanical methods to eliminate the reliance on fixed-charge, system-specific forcefields. To account for polarization at the bound state and flexibility of the ligands, we expand the multiscale nature of SEEKR by adding a quantum mechanical (QM) contribution to the innermost region representing the bound state. With existing data from our previous non-QM estimates and experimentally determined values, we compare and interpret the kinetics obtained using newly parameterized forcefields. This method provides an opportunity to achieve higher accuracy in predicting k_on and k_off.

Host-Guest System representing the QM, MM, and BD region

Lane Votapka

Appearances