Accurate geometries for “Mountain pass” regions of the Ramachandran plot using quantum chemical calculations

Abstract

Unusual local arrangements of protein in Ramachandran space are not well represented by standard geometry tools used in either protein structure refinement using simple harmonic geometry restraints or in protein simulations using molecular mechanics force fields. In contrast, quantum chemical computations using small poly-peptide molecular models can predict accurate geometries for any well-defined backbone Ramachandran orientation. For conformations along transition regions-ϕ from -60 to 60°-a very good agreement with representative high-resolution experimental X-ray (≤1.5 Å) protein structures is obtained for both backbone C -N-C angle and the nonbonded O …C distance, while "standard geometry" leads to the "clashing" of O…C atoms and Amber FF99SB predicts distances too large by about 0.15 Å. These results confirm that quantum chemistry computations add valuable support for detailed analysis of local structural arrangements in proteins, providing improved or missing data for less understood high-energy or unusual regions.

Evaluating Unexpectedly Short Non-covalent Distances in X-ray Crystal Structures of Proteins with Electronic Structure Analysis

“…32,[99][100] , including through recent curation of residue pairs for broad analysis of method accuracy in characterizing non-covalent interactions5 . Beyond these efforts, we briefly describe analysis of discrepancies between QM and MM pairwise interactions for unusually short non-covalent distances in close contacts that could help guide future force field development (Supporting InformationFigures S33-S37).…”

InterEvDock2: an expanded server for protein docking using evolutionary and biological information from homology models and multimeric inputs

“…In 15 of the total 18 targets, evolutionary information was available in the form of either co-evolution or conservation, providing key constraints to guide docking toward the correct solution. Although the InterEvDock2 pipeline was not specifically designed to handle homo-oligomeric docking, we were also among the highest ranking groups in the two joint CASP-CAPRI experiments involving mostly predictions of homodimers ( 46 , 47 ). Of note, for most CAPRI targets since 2013, only sequence information was provided to the participants.…”

When are two hydrogen bonds better than one? Accurate first-principles models explain the balance of hydrogen bond donors and acceptors found in proteins

“…59 Similar observations have recently been made in noncovalent interactions in DNA. 60 Although force elds have been noted in recent years to be broadly improving in agreement with experiment, 61 they can fail to describe noncovalent interactions essential for modeling protein structure in globular 55,62 or intrinsically disordered proteins 63 due to inherent limitations in the physics that can be captured by their functional forms. 64,65 Cooperative, strong hydrogen bonds are an exemplary subset of HBs where modeling beyond the force eld level is essential.…”