title: Simultaneous Optimization of Biomolecular Energy Functions on Features from Small Molecules and Macromolecules.
abstract: Most biomolecular modeling energy functions for structure prediction, sequence design, and molecular docking have been parametrized using existing macromolecular structural data; this contrasts molecular mechanics force fields which are largely optimized using small-molecule data. In this study, we describe an integrated method that enables optimization of a biomolecular modeling energy function simultaneously against small-molecule thermodynamic data and high-resolution macromolecular structural data. We use this approach to develop a next-generation Rosetta energy function that utilizes a new anisotropic implicit solvation model, and an improved electrostatics and Lennard-Jones model, illustrating how energy functions can be considerably improved in their ability to describe large-scale energy landscapes by incorporating both small-molecule and macromolecule data. The energy function improves performance in a wide range of protein structure prediction challenges, including monomeric structure prediction, protein-protein and protein-ligand docking, protein sequence design, and prediction of the free energy changes by mutation, while reasonably recapitulating small-molecule thermodynamic properties.
authors: Hahnbeom
authors: H
authors: Park
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center , 1100 Fairview Avenue N., Seattle, Washington 98019, United States.
authors: Philip
authors: P
authors: Bradley
authors: Per
authors: P
authors: Greisen
authors: Yuan
authors: Y
authors: Liu
authors: Vikram Khipple
authors: VK
authors: Mulligan
authors: David E
authors: DE
authors: Kim
authors: David
authors: D
authors: Baker
authors: Frank
authors: F
authors: DiMaio
mesh_terms: D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins