The VSGB 2.0 model: A next generation energy model for high resolution protein structure modeling
TLDR
Given the precision and robustness of the calculations, it is believed that the VSGB 2.0 model is suitable to tackle “real” problems, such as 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 A 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 A 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 A. 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.read more
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References
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Journal ArticleDOI
Improved Methods for Side Chain and Loop Predictions via the Protein Local Optimization Program: Variable Dielectric Model for Implicitly Improving the Treatment of Polarization Effects.
TL;DR: A novel energy model in which the internal dielectric constant of the protein is allowed to vary as a function of the interacting residues and presented a physical rationale for this model achieves qualitative improvements in the accuracy of side chain predictions with respect to experimental crystal structure and substantially reduce the RMSDs for loop predictions.
Journal ArticleDOI
What role do surfaces play in GB models? A new‐generation of surface‐generalized born model based on a novel gaussian surface for biomolecules
TL;DR: A version of the surface generalized Born (SGB) model that employs a Gaussian surface, as opposed to the van der Waals surface, is developed, and significant improvement in the energetics is seen, even in the absence of optimized empirical correction terms that were used in the latter calculations.
Journal ArticleDOI
Toward better refinement of comparative models: Predicting loops in inexact environments
TL;DR: It is hypothesized that loop refinement in homology models is much more difficult than loop reconstruction in crystal structures, in part, because side‐chain, backbone, and other structural inaccuracies surrounding the loop create a challenging sampling problem; the loop cannot be refined without simultaneously refining adjacent portions.
Journal ArticleDOI
Comparative study of generalized Born models: protein dynamics.
TL;DR: The rms deviation measure was found to be unable to distinguish the quality of the results obtained with the three different GB models, whereas the number of native hydrogen bonds and radius of gyration yielded a statistically meaningful discrimination among models.
Journal ArticleDOI
Prediction of Protein Loop Conformations using the AGBNP Implicit Solvent Model and Torsion Angle Sampling.
Anthony K. Felts,Emilio Gallicchio,Dmitriy Chekmarev,Kristina Paris,Richard A. Friesner,Ronald M. Levy +5 more
TL;DR: The results reported indicate that the OPLS-AA/AGBNP effective potential is suitable for high-resolution modeling of proteins in the final stages of homology modeling and/or protein crystallographic refinement.