Accurately computing the free energy for biological processes remains a challenging problem because both describing the interactions involved and sampling the requisite configuration space makes this problem inherently difficult. We address the sampling problem using a novel methodology we term “movable type” (MT). Conceptually it can be understood by analogy with the evolution of printing and, hence, the name movable type. For example, a common approach to the study of protein-ligand complexation involves taking a database of intact drug-like molecules and exhaustively docking them into a binding pocket. This is reminiscent of early woodblock printing where each page had to be laboriously created prior to printing a book. However, printing evolved to an approach where a database of symbols was created and then assembled using a movable type system, which allowed for the creation of all possible combinations of symbols on a given page, thereby, revolutionizing the dissemination of knowledge. Our MT method involves the identification of all atom pairs seen in biomolecules and then creating two databases: one with their associated pairwise distant dependent energies and another associated with the probability of how these pairs can combine in terms of different interactions. Combining these two databases coupled with the principles of statistical mechanics allows us to accurately estimate free energies as well as optimized molecular conformations. This method samples a wide configuration space without resorting to brute force sampling schemes involving Monte Carlo or molecular dynamics simulations making the methodology extremely efficient. Importantly, this method explores the free energy surface eliminating the need to estimate the enthalpy and entropy components individually. This methodology increases the computational efficiency of obtaining the free energy for a wide range of problems including determining the free energy of ligand binding, small molecule conformational free energy surfaces, and the protein folding problem.

Movable type method applied to the biomolecules study

249th National Meeting (2015)

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