When MELD Meets GaMD: Accelerating Biomolecular Landscape Exploration.

Abstract

We introduce Gaussian accelerated MELD (GaMELD) as a new method for exploring the energy landscape of biomolecules. GaMELD combines the strengths of Gaussian accelerated molecular dynamics (GaMD) and modeling employing limited data (MELD) to navigate complex energy landscapes. MELD uses replica-exchange molecular simulations to integrate limited and uncertain data into simulations via Bayesian inference. MELD has been successfully applied to problems of structure prediction like protein folding and complex structure prediction. However, the computational cost for MELD simulations has limited its broader applicability. The synergy of GaMD and MELD surmounts this limitation efficiently sampling the energy landscape at a lower computational cost (reducing the computational cost by a factor of 2 to six). Effectively, GaMD is used to shift energy distributions along replicas to increase the overlap in energy distributions across replicas, facilitating a random walk in replica space. We tested GaMELD on a benchmark set of 12 small proteins that have been previously studied through MELD and conventional MD. GaMELD consistently achieves accurate predictions with fewer replicas. By increasing the efficacy of replica exchange, GaMELD effectively accelerates convergence in the conformational space, enabling improved sampling across a diverse set of systems.