Efficient Biomolecular Computations Towards Applications in Drug Discovery

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Virginia Tech


Atomistic modeling and simulation methods facilitate biomedical research from many respects, including structure-based drug design. The ability of these methods to address biologically relevant problems is largely determined by the accuracy of the treatment of complex solvation effects in target biomolecules surrounded by water. The implicit solvent model – which treats solvent as a continuum with the dielectric and non-polar properties of water – offers a good balance between accuracy and speed. Simple and efficient, generalized Born (GB) model has become a widely used implicit solvent responsible for the estimation of key electrostatic interactions. The main goal of this research is to improve the accuracy of protein-ligand binding calculations in the implicit solvent framework. To address the problem (1) GBNSR6, an accurate yet efficient flavor of GB, has been thoroughly explored in the context of protein-ligand binding, (2) a global multidimensional optimization pipeline is developed to find the optimal dielectric boundary made of atomic and water probe radii specifically for protein-ligand binding calculations using GBNSR6. The pipeline includes (3) two novel post-processing steps for optimum robustness analysis and optimization landscape visualization. In the final step of this research, (4) accuracy gain the optimal dielectric boundary can bring in practice is explored on binding benchmarks, including the SARS-CoV-2 spike receptor-binding domain and the human ACE2 receptor.



Free Energy Calculation, Molecular Simulation, Drug Discovery