Understanding the thermodynamics and kinetics of protein-ligand interactions is crucial for computational drug discovery. In this project, we simulate a small host-guest system where the ligand is a single, uncharged Lennard-Jones (LJ) particle, and the binding site is an 11-particle icosahedral pocket made from the same atom type; the system is simulated in a (3.00859 nm)3 periodic box filled with 860 TIP3P waters. We first tuned the LJ parameter ε to construct a system that realistically mimics a protein-ligand binding system. Using over 80 μs of unbiased simulation, we found a value of ε = 2.5 kJ/mol produced a suitably challenging test case, with a dissociation constant of 0.19 +/- 0.04 M, and an implied timescale of 3.84 +/- 0.27ns, estimated using a 18-state Markov state model. We then tested the accuracy of different estimators when less data is used as input to the model, but sampled from biased ensembles using a combination of harmonic restraints and scaled non-bonded interactions. We compare results for the thermodynamic estimator MBAR and multi-ensemble MSM estimators dTRAM and TRAM to estimate unbiased thermodynamic and kinetic properties from the biased simulations. We also explore a method to select the optimal set of thermodynamic ensembles that will result in the most accurate estimation given the least amount of data.

Efficient estimation of binding kinetics using scaled non-bonded interactions and harmonic restraints

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.