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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Obesity and Metabolism Research » Research » Publications at this Location » Publication #309364
Title: Molecular dynamic simulations reveal the structural determinants of fatty acid binding to oxy-myoglobin

Author
item CHINTAPALLI, SREE - University Of California
item BHARDWAJ, GAURAV - University Of California
item PATEL, REEMA - University Of California
item SHAH, NATASHA - University Of California
item ANISHKIN, ANDRIY - Pennsylvania State University
item VON ROSSUM, DAMIAN - Pennsylvania State University
item PATTERSON, RANDEN - University Of California
item Adams, Sean

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/30/2015
Publication Date: 6/1/2015
Citation: Chintapalli, S.V., Bhardwaj, G., Patel, R., Shah, N., Anishkin, A., Von Rossum, D.B., Patterson, R.L., Adams, S.H. 2015. Molecular dynamic simulations reveal the structural determinants of fatty acid binding to oxy-myoglobin. PLoS One. 10(6):e0128496. doi: 10.1371/journal.pone.0128496.

Interpretive Summary: Fat is an important fuel for tissues such as muscle and heart, but when accumulated in excess can trigger inflammation and insulin resistance, risk factors for development of type 2 diabetes and metabolic syndrome. The mechanism(s) by which fatty acids are sequestered and transported in muscle have not been fully elucidated. A potential key player in this process is the muscle-abundant protein myoglobin (Mb), a member of the globin superfamily that has traditionally been viewed primarily as an oxygen carrier to support muscle fuel utilization. Indeed, there is a catalogue of empirical evidence supporting direct interaction of globins with fatty acid metabolites; however, the site(s) of binding and regulators of this process remain to be established. In this study, we employed a computational strategy to elucidate the structural determinants of palmitic acid binding to Mb. Sequence analysis and docking simulations with a horse (Equus caballus) structural Mb reference reveals a fatty acid-binding site in the hydrophobic cleft near the heme (oxygen-binding) region in Mb. Moreover, our simulations predict that the oxygen molecule and heme group are required for additional hydrophobic interactions. Taken together, these findings support the idea that Mb acts as a muscle transporter for fatty acid only when it is in the oxygenated state, which could help support healthy skeletal muscle and heart muscle management of fat storage and burning.

Technical Abstract: The mechanism(s) by which fatty acids are sequestered and transported in muscle have not been fully elucidated. A potential key player in this process is the protein myoglobin (Mb). Indeed, there is a catalogue of empirical evidence supporting direct interaction of globins with fatty acid metabolites; however, the site(s) of binding and regulators remains to be established. In this study, we employed a computational strategy to elucidate the structural determinants of palmitic acid binding to Mb. Sequence analysis and docking simulations with horse (Equus caballus) structural Mb reference reveals a fatty acid-binding site in the hydrophobic cleft near the heme region in Mb. Molecular dynamic analysis of protein-ligand interaction demonstrates that the distal histidine group of oxy-myoglobin undergoes a 90º rotation to facilitate the spontaneous entry and deeper penetration of palmitic acid. This ligand attains a “U” shaped structure similar to its conformation in pockets of other fatty acid-binding proteins. Specifically, we found that the carboxyl head group of palmitic acid coordinates with the amino groups of Lys45 and Lys63, and the alkyl tail is supported by hydrophobic residues Leu29, Phe33, Phe43, Phe46, Val67, Val68 and Ile107. Moreover, our simulations predict that the oxygen molecule and heme group are required for additional hydrophobic interactions. Taken together, these findings not only reveal a dynamic but stable binding, but also support the idea that Mb acts as a muscle transporter for fatty acid when it is in the oxygenated state and releases fatty acid when Mb converts to deoxygenated state.