Molecular dynamic simulations reveal the structural determinants of fatty acid binding to oxy-myoglobin

Sree V. Chintapalli, Gaurav Bhardwaj, Reema Patel, Natasha Shah, Randen L. Patterson, Damian B. Van Rossum, Andriy Anishkin, Sean H. Adams

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere0128496
JournalPloS one
Volume10
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

myoglobin
molecular dynamics
Myoglobin
Molecular Dynamics Simulation
Molecular dynamics
Fatty Acids
fatty acids
Computer simulation
Palmitic Acid
Oleic Acid
palmitic acid
oleic acid
heme
Heme
Horses
Muscle
Tail
tail
horses
fatty acid-binding proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Chintapalli, S. V., Bhardwaj, G., Patel, R., Shah, N., Patterson, R. L., Van Rossum, D. B., ... Adams, S. H. (2015). Molecular dynamic simulations reveal the structural determinants of fatty acid binding to oxy-myoglobin. PloS one, 10(6), [e0128496]. https://doi.org/10.1371/journal.pone.0128496
Chintapalli, Sree V. ; Bhardwaj, Gaurav ; Patel, Reema ; Shah, Natasha ; Patterson, Randen L. ; Van Rossum, Damian B. ; Anishkin, Andriy ; Adams, Sean H. / Molecular dynamic simulations reveal the structural determinants of fatty acid binding to oxy-myoglobin. In: PloS one. 2015 ; Vol. 10, No. 6.
@article{0a9353d4c20241539bfd5c27ad8d2ec1,
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.",
author = "Chintapalli, {Sree V.} and Gaurav Bhardwaj and Reema Patel and Natasha Shah and Patterson, {Randen L.} and {Van Rossum}, {Damian B.} and Andriy Anishkin and Adams, {Sean H.}",
year = "2015",
month = "6",
day = "1",
doi = "10.1371/journal.pone.0128496",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

Chintapalli, SV, Bhardwaj, G, Patel, R, Shah, N, Patterson, RL, Van Rossum, DB, Anishkin, A & Adams, SH 2015, 'Molecular dynamic simulations reveal the structural determinants of fatty acid binding to oxy-myoglobin', PloS one, vol. 10, no. 6, e0128496. https://doi.org/10.1371/journal.pone.0128496

Molecular dynamic simulations reveal the structural determinants of fatty acid binding to oxy-myoglobin. / Chintapalli, Sree V.; Bhardwaj, Gaurav; Patel, Reema; Shah, Natasha; Patterson, Randen L.; Van Rossum, Damian B.; Anishkin, Andriy; Adams, Sean H.

In: PloS one, Vol. 10, No. 6, e0128496, 01.06.2015.

Research output: Contribution to journalArticle

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84934991264&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84934991264&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0128496

DO - 10.1371/journal.pone.0128496

M3 - Article

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 6

M1 - e0128496

ER -