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Accurate and efficient simulation of the thermodynamics and kinetics of protein–ligand interactions is crucial for computational drug discovery. Multiensemble Markov Model (MEMM) estimators can provide estimates of both binding rates and affinities from collections of short trajectories but have not been systematically explored for situations when a ligand is decoupled through scaling of non-bonded interactions. In this work, we compare the performance of two MEMM approaches for estimating ligand binding affinities and rates: (1) the transition-based reweighting analysis method (TRAM) and (2) a Maximum Caliber (MaxCal) based method. As a test system, we construct a small host–guest system where the ligand is a single uncharged Lennard-Jones (LJ) particle, and the receptor is an 11-particle icosahedral pocket made from the same atom type. To realistically mimic a protein–ligand binding system, the LJ ϵ parameter was tuned, and the system was placed in a periodic box with 860 TIP3P water molecules. A benchmark was performed using over 80 µs of unbiased simulation, and an 18-state Markov state model was used to estimate reference binding affinities and rates. We then tested the performance of TRAM and MaxCal when challenged with limited data. Both TRAM and MaxCal approaches perform better than conventional Markov state models, with TRAM showing better convergence and accuracy. We find that subsampling of trajectories to remove time correlation improves the accuracy of both TRAM and MaxCal and that in most cases, only a single biased ensemble to enhance sampled transitions is required to make accurate estimates.

 

SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression and replication that depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate 0.1 seconds of the viral proteome. Our adaptive sampling simulations predict dramatic opening of the apo spike complex, far beyond that seen experimentally, explaining and predicting the existence of ‘cryptic’ epitopes. Different spike variants modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also discover dramatic conformational changes across the proteome, which reveal over 50 ‘cryptic’ pockets that expand targeting options for the design of antivirals. All data and models are freely available online, providing a quantitative structural atlas.