Long-timescale molecular-dynamics simulations of the major urinary protein provide atomistic interpretations of the unusual thermodynamics of ligand binding.

Biophysical Journal
Julie Roy, Charles A Laughton

Abstract

The mouse major urinary protein (MUP) has proved to be an intriguing test bed for detailed studies on protein-ligand recognition. NMR, calorimetric, and modeling investigations have revealed that the thermodynamics of ligand binding involve a complex interplay between competing enthalpic and entropic terms. We performed six independent, 1.2 micros molecular-dynamics simulations on MUP--three replicates on the apo-protein, and three on the complex with the pheromone isobutylmethoxypyrazine. Our findings provide the most comprehensive picture to date of the structure and dynamics of MUP, and how they are modulated by ligand binding. The mechanical pathways by which amino acid side chains can transmit information regarding ligand binding to surface loops and either increase or decrease their flexibility (entropy-entropy compensation) are identified. Dewetting of the highly hydrophobic binding cavity is confirmed, and the results reveal an aspect of ligand binding that was not observed in earlier, shorter simulations: bound ligand retains extensive rotational freedom. Both of these features have significant implications for interpretations of the entropic component of binding. More generally, these simulations test the ability of c...Continue Reading

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Citations

Nov 16, 2011·Quarterly Reviews of Biophysics·Jeff Wereszczynski, J Andrew McCammon
Jan 11, 2011·Journal of Chemical Information and Modeling·Yat T Tang, Garland R Marshall
Jan 28, 2012·Journal of the American Chemical Society·Bjoern E S OlaussonAlexander Vogel
Nov 10, 2011·Journal of Biomolecular Structure & Dynamics·Ragothaman M YennamalliTaner Z Sen
Mar 20, 2014·Journal of Molecular Graphics & Modelling·Elena Ermakova, Rauf Kurbanov
Dec 17, 2019·Biophysical Chemistry·Homero Gómez-VelascoEnrique García-Hernández
Apr 29, 2015·Journal of Medicinal Chemistry·Stefan GeschwindnerPatrik Johansson
Oct 29, 2014·The Journal of Physical Chemistry. B·Olof AllnérLennart Nilsson
Mar 13, 2012·Journal of Chemical Theory and Computation·Oliver CarrilloModesto Orozco

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