First Principles-Based Calculations of Free Energy of Binding: Application to Ligand Binding in a Self-Assembling Superstructure.

The accurate prediction of ligand binding affinities to a protein remains a desirable goal of computational biochemistry. Many available methods use molecular mechanics (MM) to describe the system, however, MM force fields cannot fully describe the complex interactions involved in binding, specifically electron transfer and polarization. First principles approaches can fully account for these interactions, and with the development of linear-scaling first principles programs, it is now viable to apply first principles calculations to systems containing tens of thousands of atoms. In this paper, a quantum mechanical Poisson-Boltzmann surface area approach is applied to a model of a protein-ligand binding cavity, the "tennis ball" dimer. Results obtained from this approach demonstrate considerable improvement over conventional molecular mechanics Poisson-Boltzmann surface area due to the more accurate description of the interactions in the system. For the first principles calculations in this study, the linear-scaling density functional theory program ONETEP is used, allowing the approach to be applied to receptor-ligand complexes of pharmaceutical interest that typically include thousands of atoms.

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