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Multiple molecular dynamics simulations of human LOX-1 and Trp150Ala mutant reveal the structural determinants
Federico Iacovelli1, Fabio Giovanni Tucci1, Gabriele Macari1
1Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
Abstract:
Multiple classical molecular dynamics simulations have been applied to the human LOX-1 receptor to clarify the role of the Trp150Ala mutation in the loss of binding activity. Results indicate that the substitution of this crucial residue, located at the dimer interface, markedly disrupts the wild-type receptor dynamics. The mutation causes an irreversible rearrangement of the subunits interaction pattern that in the wild-type protein allows the maintaining of a specific symmetrical motion of the monomers. The subunits dislocation determines a loss of linearity of the arginines residues composing the basic spine and a consequent alteration of the long-range electrostatic attraction of the substrate. Moreover, the anomalous subunits arrangement observed in the mutated receptor also affects the integrity of the hydrophobic tunnel, actively involved in the short-range hydrophobic recognition of the substrate. The combined effect of these structural rearrangements generates the impairing of the receptor function.
Insights
The Trp150Ala mutation disrupts the LOX-1 receptor
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- The LOX-1 receptor plays a critical role in cellular processes.
- Understanding mutations affecting LOX-1 receptor function is crucial for biological research.
Purpose of the Study:
- To investigate the impact of the Trp150Ala mutation on the human LOX-1 receptor's binding activity.
- To elucidate the structural and dynamic changes induced by this mutation.
Main Methods:
- Classical molecular dynamics simulations were employed.
- Analysis focused on receptor dynamics, subunit interactions, and key residue linearity.
Main Results:
- The Trp150Ala mutation disrupts wild-type receptor dynamics at the dimer interface.
- It causes irreversible subunit rearrangement, affecting monomer motion and basic spine linearity.
- Altered electrostatic attraction and hydrophobic tunnel integrity were observed.
Conclusions:
- The Trp150Ala mutation impairs LOX-1 receptor function through significant structural and dynamic alterations.
- These changes affect both long-range electrostatic and short-range hydrophobic substrate interactions.
