Free energy changes at constant pressure, ΔG, dictates the spontaneity (ΔG &lt;0) of a reaction. The existing methods to compute binding free energy changes often rely on the ensemble of protein conformations – generated using molecular dynamics simulations – a time-consuming process. Here we develop a novel approach for fast computation of free energy changes based on the hypothesis that free energy can be computed using two-state protein conformations. Protein conformational changes were quantitatively captured as a summation of protein microenvironments changes (ΔrHpy) of individual amino acids during biochemical reactions. ΔrHpy was derived based on log P values (P is the partition coefficient for small molecules). This hypothesis is tested on 28 protein-ligand/drug complexes of SARS-COV-2/SARS-COV main proteases reported in PDB database. The computed ΔG were compared with published inhibitory concentration (IC50) and inhibitory constant (Ki) values, as the indirect measures of ΔG – the correlation coefficients range from 0.75 to 0.88. The parameter was exploited to explain the feasibility of Cu(II)-binding reaction to wild-type peroxiredoxin-like peroxidase, DJ1 protein. The same reaction was predicted as unfeasible for oxidized forms. The computational time for two-state based prediction on DJ1 protein was in seconds in contrast to ensemble-based prediction in several days. This fast free energy computation method can be used for initial drug screening, subject to validation on larger drug datasets.

Novel approach for fast computation of free energy changes based on two-state protein conformations: Hypothesis tested on protein-drug complexes

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