Alkyl Isocyanides Serve as Transition State Analogs for Ligand Entry and Exit in Myoglobin†

• Published in: Biochemistry
• Main Authors: Blouin, George C., Schweers, Rachel L., Olson, John S.
• Format: Text
• Language: English
• Published: 2010
• Subjects: Article; Sperm whale
• Online Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102008; http://www.ncbi.nlm.nih.gov/pubmed/20476741; https://doi.org/10.1021/bi1001745

Alkyl isocyanides (CNRs) identify pathways for diatomic ligand movement into and out of Mb, with their side chains acting as transition state analogs. The bound alkyl groups point either into the back of the distal pocket (in conformation, νCN ≈ 2070–2090 cm−1), which allows hydrogen bond donation from His64(E7) to the isocyano group, or toward solvent through an open His(E7) channel (out conformation, νCN ≈ 2110–2130 cm−1), which prevents polar interactions with the isocyano atoms. Fractions of the in conformer (Fin) were measured by FTIR spectroscopy for methyl through n-pentyl isocyanide bound to a series of 20 different distal pocket mutants of sperm whale myoglobin and found to be governed by the ease of rotation of the His(E7) side chain, distal pocket volume and steric interactions, and, for the longer isocyanides, the unfavorable hydrophobic effect of placing their terminal carbon atoms into the solvent phase in the out conformation. There are strong correlations between the fraction of in conformer, Fin, for long chain MbCNR complexes measured by FTIR spectroscopy, the fraction of geminate recombination of photodissociated O2, and the bimolecular rates of O2 entry into the distal pocket. These correlations indicate that alkyl isocyanides serve as transition state analogs for the movement of O2 into and out of the binding pocket of Mb.