UC San Diego

Advancements in computational and methodological approaches have revolutionized our understanding of complex biomolecular systems. This dissertation presents innovative computational methodologies for accurately predicting the kinetics and thermodynamics of complex biomolecular systems, aiming to provide efficient alternatives to traditional long-scale molecular dynamics (MD) simulations. The research focuses on multiscale milestoning approaches, weighted ensemble methods, deep learning algorithms, and obtaining precise force field parameters as efficient alternatives to traditional MD simulations. This work presents advancements accomplished in the SEEKR (Simulation enabled estimation of kinetic rates) framework, an advanced tool for estimating biomolecular kinetics and thermodynamics, particularly predicting ligand-receptor (un)binding estimates. The incorporation of quantum mechanical force field reparameterization through the QMrebind tool marks a significant step in enhancing the accuracy of milestoning simulations. Additionally, it explores hybrid methods such as GaMD-WE (Gaussian-accelerated MD with the weighted ensemble) and DeepWEST (Deep learning with the weighted ensemble simulation toolkit), which synergize the benefits of enhanced sampling methods and deep learning for more effective kinetic and thermodynamic sampling of biomolecules. These methodologies significantly reduce computational demands while accurately predicting complex biomolecular processes, including receptor-ligand binding/unbinding, protein-protein interactions, and (un)folding, offering substantial contributions to computational biology and enhancing the understanding of biomolecular behavior with greater efficiency and accuracy.