Identification and Scoring of Partial Covalent Interactions in Proteins and Protein Ligand Complexes

Abstract

Partial covalent interactions (PCI) such as hydrogen bonds, salt bridges, cation-π, and π-π interactions contribute to protein thermostability. Algorithms that identify PCIs rely on pairwise atom-atom angles and distances, neglecting that PCIs occur between an electron deficient hydrogen and an electron orbital of the accepting atom. Accurate chemical representation of PCIs will improve protein thermostabilization via computational protein design. We have introduced orbital based chemical descriptors for PCIs into the Rosetta Suite of Protein Structure Prediction Algorithms. Native-like geometries of hydrogen bonds, salt bridges, cation-pi, and pi-pi interactions are recapitulated during minimization of protein conformation. Additionally, a series of benchmarks designed to test the accuracy of the score function show that incorporation of partial covalent interaction increases discrimination of models built with the new score functions.