title: Molecular dynamic simulations reveal the structural determinants of Fatty Acid binding to oxy-myoglobin.
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 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.
authors.affiliation: Arkansas Children's Nutrition Center, and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Sree V
authors.initials: SV
authors.lastname: Chintapalli
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bhardwaj
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, California, United States of America; Department of Physiology and Membrane Biology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Reema
authors.initials: R
authors.lastname: Patel
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, California, United States of America; Department of Physiology and Membrane Biology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Natasha
authors.initials: N
authors.lastname: Shah
authors.affiliation: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Davis, California, United States of America; Department of Physiology and Membrane Biology, School of Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Randen L
authors.initials: RL
authors.lastname: Patterson
authors.affiliation: Center for Computational Proteomics, The Pennsylvania State University, State College, Pennsylvania, United States of America; Department of Biology, The Pennsylvania State University, State College, Pennsylvania, United States of America.
authors.forename: Damian B
authors.initials: DB
authors.lastname: van Rossum
authors.affiliation: Department of Biology, University of Maryland, College Park, Maryland, United States of America.
authors.forename: Andriy
authors.initials: A
authors.lastname: Anishkin
authors.affiliation: Arkansas Children's Nutrition Center, and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Sean H
authors.initials: SH
authors.lastname: Adams
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D006736:Horses; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009211:Myoglobin / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid
chemical_list: D005227:Fatty Acids; D009211:Myoglobin; C017595:oxymyoglobin