Frequent side chain methyl carbon-oxygen hydrogen bonding in proteins revealed by computational and stereochemical analysis of neutron structures

The propensity of backbone C atoms to engage in carbon-oxygen (CH center dot center dot center dot O) hydrogen bonding is well-appreciated in protein structure, but side chain CH center dot center dot center dot O hydrogen bonding remains largely uncharacterized. The extent to which side chain methyl groups in proteins participate in CH center dot center dot center dot O hydrogen bonding is examined through a survey of neutron crystal structures, quantum chemistry calculations, and molecular dynamics simulations. Using these approaches, methyl groups were observed to form stabilizing CH center dot center dot center dot O hydrogen bonds within protein structure that are maintained through protein dynamics and participate in correlated motion. Collectively, these findings illustrate that side chain methyl CH center dot center dot center dot O hydrogen bonding contributes to the energetics of protein structure and folding. Proteins 2015; 83:403-410. (c) 2014 Wiley Periodicals, Inc.