Protein side chain conformation predictions with an MMGBSA energy function

Abstract

The prediction of protein side chain conformations from backbone coordinates is an important task in structural biology, with applications in structure prediction and protein design. It is a difficult problem due to its combinatorial nature. We study the performance of an "MMGBSA" energy function, implemented in our protein design program Proteus, which combines molecular mechanics terms, a Generalized Born and Surface Area (GBSA) solvent model, with approximations that make the model pairwise additive. Proteus is not a competitor to specialized side chain prediction programs due to its cost, but it allows protein design applications, where side chain prediction is an important step and MMGBSA an effective energy model. We predict the side chain conformations for 18 proteins. The side chains are first predicted individually, with the rest of the protein in its crystallographic conformation. Next, all side chains are predicted together. The contributions of individual energy terms are evaluated and various parameterizations are compared. We find that the GB and SA terms, with an appropriate choice of the dielectric constant and surface energy coefficients, are beneficial for single side chain predictions. For the prediction of all side chains, however, errors due to the pairwise additive approximation overcome the improvement brought by these terms. We also show the crucial contribution of side chain minimization to alleviate the rigid rotamer approximation. Even without GB and SA terms, we obtain accuracies comparable to SCWRL4, a specialized side chain prediction program. In particular, we obtain a better RMSD than SCWRL4 for core residues (at a higher cost), despite our simpler rotamer library. Proteins 2016; 84:803-819. © 2016 Wiley Periodicals, Inc.

2-Methoxyestradiol Affects Mitochondrial Biogenesis Pathway and Succinate Dehydrogenase Complex Flavoprotein Subunit A in Osteosarcoma Cancer Cells

“…Specifically, molecular docking of 2-ME was performed on the two possible binding sites, the canonical inhibitor site (NAD+ catalytic binding site in the C-terminus) and/or the allosteric site (N-terminus region). The best docking poses of 2-ME were selected and analysis of the molecular mechanics energies combined with the generalized Born and surface area continuum solvation (MMGBSA) was performed to evaluate the enthalpy and free energy contributions to the binding process (53)(54)(55). Finally, molecular dynamics simulations were performed to explore the stability of the ligand-protein complex and to evaluate the time evolution of the main host-guest interactions.…”

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“…Side chains more than 20 Å from the ligand were held fixed. The other side chains were allowed to explore rotamers, taken from the Tuffery library, augmented to allow multiple orientations for certain hydrogen atoms [42,43]. Side chains 13 and 301 were allowed to mutate into the following 14 types: ACDEHIKLMNQSTV; position 260 was allowed to mutate into the same types, except that Tyr replaced Asp.…”

Adaptive landscape flattening allows the design of both enzyme:substrate binding and catalytic power

“…The protein backbone and side chains more than 20Å from the ligand were held fixed. The other side chains were allowed to explore rotamers, taken from the Tuffery library, augmented to allow multiple orientations for certain hydrogen atoms [42,43]. Side chains 13 and 301 were allowed to mutate into the following 14 types: ACDEGHIKLMQSTV; position 260 was allowed to mutate into the same types, except that Tyr replaced Asp.…”

“…The protein backbone and side chains more than 20Å from the ligand were held fixed. The other side chains were allowed to explore rotamers [42,43]. Side chains 13, 256 and 297 were allowed to mutate into all types except Gly or Pro, for a total of 5832 possible sequences in all.…”