Potential functions for hydrogen bonds in protein structure prediction and design.

Abstract

Hydrogen bonds are an important contributor to free energies of biological macromolecules and macromolecular complexes, and hence an accurate description of these interactions is important for progress in biomolecular modeling. A simple description of the hydrogen bond is based on an electrostatic dipole-dipole interaction involving hydrogen-donor and acceptor-acceptor base dipoles, but the physical nature of hydrogen bond formation is more complex. At the most fundamental level, hydrogen bonding is a quantum mechanical phenomenon with contributions from covalent effects, polarization, and charge transfer. Recent experiments and theoretical calculations suggest that both electrostatic and covalent components determine the properties of hydrogen bonds. Likely, the level of rigor required to describe hydrogen bonding will depend on the problem posed. Current approaches to modeling hydrogen bonds include knowledge-based descriptions based on surveys of hydrogen bond geometries in structural databases of proteins and small molecules, empirical molecular mechanics models, and quantum mechanics-based electronic structure calculations. Ab initio calculations of hydrogen bonding energies and geometries accurately reproduce energy landscapes obtained from the distributions of hydrogen bond geometries observed in protein structures. Orientation-dependent hydrogen bonding potentials were found to improve the quality of protein structure prediction and refinement, protein-protein docking, and protein design.