TY - JOUR
T1 - Molecular dynamic simulations reveal the structural determinants of fatty acid binding to oxy-myoglobin
AU - Chintapalli, Sree V.
AU - Bhardwaj, Gaurav
AU - Patel, Reema
AU - Shah, Natasha
AU - Patterson, Randen L.
AU - Van Rossum, Damian B.
AU - Anishkin, Andriy
AU - Adams, Sean H.
N1 - Funding Information:
The authors wish to thank Dr. Trina A. Knotts for helpful discussions. This work was supported by the Searle Young Investigators Award (RLP), start-up money from UC Davis (RLP), NIH R01 GM087410-01 (RLP, DBR), intramural USDA-ARS Project 5306-51530-019-00 (SHA) and NIH-NIDDK R01DK078328-01 (SHA). This project was also supported by a grant from the Pennsylvania Department of Health using Tobacco Settlement Funds (DBR). The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations or conclusions. The USDA is an Equal Opportunity provider and employer.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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 binding pocket and regulation of the interaction remains to be established. In this study, we employed a computational strategy to elucidate the structural determinants of fatty acids (palmitic & oleic 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 region in Mb. Both palmitic acid and oleic acid attain a "U" shaped structure similar to their conformation in pockets of other fatty acid-binding proteins. Specifically, we found that the carboxyl head group of palmitic acid coordinates with the amino group of Lys45, whereas the carboxyl group of oleic acid coordinates with both the amino groups of Lys45 and Lys63. The alkyl tails of both fatty acids are supported by surrounding hydrophobic residues Leu29, Leu32, Phe33, Phe43, Phe46, Val67, Val68 and Ile107. In the saturated palmitic acid, the hydrophobic tail moves freely and occasionally penetrates deeper inside the hydrophobic cleft, making additional contacts with Val28, Leu69, Leu72 and Ile111. Our simulations reveal a dynamic and stable binding pocket in which the oxygen molecule and heme group in Mb are required for additional hydrophobic interactions. Taken together, these findings support a mechanism in which 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.
AB - 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 binding pocket and regulation of the interaction remains to be established. In this study, we employed a computational strategy to elucidate the structural determinants of fatty acids (palmitic & oleic 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 region in Mb. Both palmitic acid and oleic acid attain a "U" shaped structure similar to their conformation in pockets of other fatty acid-binding proteins. Specifically, we found that the carboxyl head group of palmitic acid coordinates with the amino group of Lys45, whereas the carboxyl group of oleic acid coordinates with both the amino groups of Lys45 and Lys63. The alkyl tails of both fatty acids are supported by surrounding hydrophobic residues Leu29, Leu32, Phe33, Phe43, Phe46, Val67, Val68 and Ile107. In the saturated palmitic acid, the hydrophobic tail moves freely and occasionally penetrates deeper inside the hydrophobic cleft, making additional contacts with Val28, Leu69, Leu72 and Ile111. Our simulations reveal a dynamic and stable binding pocket in which the oxygen molecule and heme group in Mb are required for additional hydrophobic interactions. Taken together, these findings support a mechanism in which 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.
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U2 - 10.1371/journal.pone.0128496
DO - 10.1371/journal.pone.0128496
M3 - Article
C2 - 26030763
AN - SCOPUS:84934991264
SN - 1932-6203
VL - 10
JO - PloS one
JF - PloS one
IS - 6
M1 - e0128496
ER -