Noncovalent π Interactions in Mutated Aquomet-Myoglobin Proteins: A QM/MM and Local Vibrational Mode Study.

Protein dynamics and function is strongly connected to the energy flow taking place. Myoglobin (Mb) and its mutations are ideal systems to study the process of vibrational energy transfer (VET) at the molecular level. Anti-Stokes ultraviolet resonance Raman studies using a tryptophan (Trp) probe, introduced at different Mb positions by amino acid replacement, have suggested that the amount of VET depends on the position of the Trp probe relative to the heme group. Inspired by this experimental work, we explored the strength of noncovalent π interactions, as well as covalent interactions for both the axial and distal ligands bound to iron in aquomet-Mb with the local vibrational mode analysis (LMA), originally developed by Konkoli and Cremer. Two sets of noncovalent interactions were investigated: (1) the interaction between the water ligand and Trp rings and (2) the interaction between the Trp and the porphyrin rings of the heme group. We assessed the strength of these noncovalent interactions via a special local mode force constant. Various Trp-modified water-bound ferric Mb proteins in the ground state were studied (6 in total) using gas-phase and QM/MM calculations followed by LMA. Our results disclose that VET is indeed dependent on the position of the Trp probe relative to the heme group but also on the tautomeric nature of distal histidine. They provide new guidelines on how to assess noncovalent π interactions in proteins utilizing LMA and how to use these data to explore VET, and more generally protein dynamics and function.