The VSGB 2.0 model: A next generation energy model for high resolution protein structure modeling

TLDR

The study introduces VSGB 2.0, a novel energy model for high‑resolution protein structure modeling that incorporates an optimized implicit solvent and physics‑based corrections for hydrogen bonding, π‑π, self‑contact, and hydrophobic interactions. VSGB 2.0 parameters were fitted to a crystallographic database of 2,239 single side‑chain and 100 11‑13 residue loop predictions, and the model was validated by predicting 115 super‑long loops up to 20 residues using advanced sampling and a robust protonation state algorithm. The model achieved high accuracy, with all lowest‑energy conformations having backbone RMSDs better than 2.0 Å and average RMSDs ranging from 0.51 to 1.59 Å across 14–20 residue loops, demonstrating its suitability for biological function modeling and structure‑based drug discovery.

Abstract

A novel energy model (VSGB 2.0) for high resolution protein structure modeling is described, which features an optimized implicit solvent model as well as physics-based corrections for hydrogen bonding, π-π interactions, self-contact interactions, and hydrophobic interactions. Parameters of the VSGB 2.0 model were fit to a crystallographic database of 2239 single side chain and 100 11-13 residue loop predictions. Combined with an advanced method of sampling and a robust algorithm for protonation state assignment, the VSGB 2.0 model was validated by predicting 115 super long loops up to 20 residues. Despite the dramatically increasing difficulty in reconstructing longer loops, a high accuracy was achieved: all of the lowest energy conformations have global backbone RMSDs better than 2.0 Å from the native conformations. Average global backbone RMSDs of the predictions are 0.51, 0.63, 0.70, 0.62, 0.80, 1.41, and 1.59 Å for 14, 15, 16, 17, 18, 19, and 20 residue loop predictions, respectively. When these results are corrected for possible statistical bias as explained in the text, the average global backbone RMSDs are 0.61, 0.71, 0.86, 0.62, 1.06, 1.67, and 1.59 Å. Given the precision and robustness of the calculations, we believe that the VSGB 2.0 model is suitable to tackle "real" problems, such as biological function modeling and structure-based drug discovery.