期刊
BIOPHYSICAL JOURNAL
卷 99, 期 1, 页码 218-226出版社
CELL PRESS
DOI: 10.1016/j.bpj.2010.03.055
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资金
- Office of Science and Technology through the Engineering and Physical Sciences Research Council [EP/G004455/1]
- Biotechnology and Biological Sciences Research Council [BBF0114071]
- Engineering and Physical Sciences Research Council [EP/G004455/1] Funding Source: researchfish
- EPSRC [EP/G004455/1] Funding Source: UKRI
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 mu s 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 current molecular simulation methods to produce a reliable and reproducible picture of protein dynamics on the microsecond timescale.
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