Multibasin Quasi-Harmonic Approach for the Calculation of the Configurational Entropy of Small Molecules in Solution

Entropy is a key thermodynamic property governing most biomolecular processes, including binding. Nonetheless, quantification of the configurational entropy of a single molecule in solution remains a grand challenge. Here, we present an original approach for the calculation of absolute molecular entropies based on the analysis of converged molecular dynamics (MD) simulations. Our method, named quasi-harmonic multibasin (QHMB), relies on a multibasin decomposition of the simulated trajectory by root-mean-square deviation clustering and subsequent quasi-harmonic analysis (QHA) of extracted sub-trajectories. Last, the entropy of the landscape is evaluated using the Gibbs formula. Because of the nature of QHA, this method is directly applicable to explicit-solvent simulations to access configurational entropies in solution. When compared with calorimetric data from NIST, QHMB is shown to predict absolute entropies in the gas phase for 23 small molecules with a root-mean-squared error of 0.36 kcal/mol from the experiments. In addition, the introduction of a QHMB correction in MM/GBSA calculations to account for the ligand configurational entropy loss on binding is shown to improve the correlation between calculated and experimental binding affinities with R² increasing from 0.67 to 0.78. Because this entropy correction penalizes large and flexible ligands more strongly, it might be useful to reduce the false-positive rate in virtual screening. The availability of an automatic procedure to compute QHMB entropies makes it a new available tool in the field of drug discovery.