Related papers: Improving sampling of binding free energy differen…
Relative free energy calculations are now widely used in academia and industry, but the accuracy is often limited by poor sampling of the complexes conformational ensemble. To address this, we have developed a novel method termed…
Generalized ensemble methods such as Hamiltonian replica exchange (HREX) and expanded ensemble (EE) have been shown effective in free energy calculations for various contexts, given their ability to circumvent free energy barriers via…
The widespread popularity of replica exchange and expanded ensemble algorithms for simulating complex molecular systems in chemistry and biophysics has generated much interest in enhancing phase space mixing of these protocols, thus…
For many macromolecular systems the accurate sampling of the relevant regions on the potential energy surface cannot be obtained by a single, long Molecular Dynamics (MD) trajectory. New approaches are required to promote more efficient…
We present an extension of Alchemical Transfer Method (ATM) for the estimation of relative binding free energies of molecular complexes applicable to conventional as well as scaffold-hopping alchemical transformations. The method, named…
The computational study of conformational transitions in RNA and proteins with atomistic molecular dynamics often requires suitable enhanced sampling techniques. We here introduce a novel method where concurrent metadynamics are integrated…
We present receptor hopping and receptor swapping free energy estimation protocols based on the Alchemical Transfer Method (ATM) to model the binding selectivity of a set of ligands to two arbitrary receptors. The receptor hopping protocol,…
Simulations of protein folding and protein association happen on timescales that are orders of magnitude larger than what can typically be covered in all-atom molecular dynamics simulations. Use of low-resolution models alleviates this…
The accurate sampling of protein dynamics is an ongoing challenge despite the utilization of High-Performance Computers (HPC) systems. Utilizing only "brute force" MD simulations requires an unacceptably long time to solution. Adaptive…
Free energy perturbation (FEP) is frequently used to evaluate the free energy change of a biological process, e.g. the drug binding free energy or the ligand solvation free energy. Due to the sampling inefficiency, FEP is often employed…
The Alchemical Transfer Method (ATM) is herein validated against the relative binding free energies of a diverse set of protein-ligand complexes. We employed a streamlined setup workflow, a bespoke force field, and the AToM-OpenMM software…
Replica Exchange (RE) simulations have emerged as an important algorithmic tool for the molecular sciences. RE simulations involve the concurrent execution of independent simulations which infrequently interact and exchange information. The…
Predicting the binding affinity between small molecules and target macromolecules while combining both speed and accuracy, is a cornerstone of modern computational drug discovery which is critical for accelerating therapeutic development.…
This paper considers a class of reinforcement learning problems, which involve systems with two types of states: stochastic and pseudo-stochastic. In such systems, stochastic states follow a stochastic transition kernel while the…
One of the key limitations of Molecular Dynamics simulations is the computational intractability of sampling protein conformational landscapes associated with either large system size or long timescales. To overcome this bottleneck, we…
Accurate absolute binding free energy (ABFE) calculations can reduce the time and cost of identifying drug candidates from a diverse pool of molecules that may have been overlooked experimentally. These calculations typically employ…
Model-based deep reinforcement learning has achieved success in various domains that require high sample efficiencies, such as Go and robotics. However, there are some remaining issues, such as planning efficient explorations to learn more…
We present the Alchemical Transfer with Coordinate Swapping (ATS) method to enable the calculation of the relative binding free energies between large congeneric ligands and single-point mutant peptides to protein receptors with the…
Performing alchemical transformations, in which one molecular system is nonphysically changed to another system, is a popular approach adopted in performing free energy calculations associated with various biophysical processes, such as…
The free energy landscapes of several fundamental processes are characterized by high barriers separating long-lived metastable states. In order to explore these type of landscapes enhanced sampling methods are used. While many such methods…