Protein surface roughness accounts for binding free energy of Plasmepsin II-ligand complexes.

Autor: Valdés-Tresanco ME; Computational Biology and Biomolecular Dynamics Laboratory, Center for Proteins Studies, Faculty of Biology, University of Havana, Havana, Cuba., Valdés-Tresanco MS; Faculty of Biology, University of Havana, Havana, Cuba., Valiente PA; Computational Biology and Biomolecular Dynamics Laboratory, Center for Proteins Studies, Faculty of Biology, University of Havana, Havana, Cuba., Cocho G; C3 Complex Systems Institute and UNAM Physics Institute, Mexico., Mansilla R; Center for Interdisciplinary Investigations of Humanities and Sciences, UNAM, Mexico., Nieto-Villar JM; Department of Chemical-Physics, Faculty of Chemistry and H. Poincare Group of Complex Systems, Faculty of Physics, University of Havana, Havana, Cuba.
Jazyk: angličtina
Zdroj: Journal of molecular recognition : JMR [J Mol Recognit] 2018 Jan; Vol. 31 (1). Date of Electronic Publication: 2017 Sep 12.
DOI: 10.1002/jmr.2661
Abstrakt: The calculation of absolute binding affinities for protein-inhibitor complexes remains as one of the main challenges in computational structure-based ligand design. The present work explored the calculations of surface fractal dimension (as a measure of surface roughness) and the relationship with experimental binding free energies of Plasmepsin II complexes. Plasmepsin II is an attractive target for novel therapeutic compounds to treat malaria. However, the structural flexibility of this enzyme is a drawback when searching for specific inhibitors. Concerning that, we performed separate explicitly solvated molecular dynamics simulations using the available high-resolution crystal structures of different Plasmepsin II complexes. Molecular dynamics simulations allowed a better approximation to systems dynamics and, therefore, a more reliable estimation of surface roughness. This constitutes a novel approximation in order to obtain more realistic values of fractal dimension, because previous works considered only x-ray structures. Binding site fractal dimension was calculated considering the ensemble of structures generated at different simulation times. A linear relationship between binding site fractal dimension and experimental binding free energies of the complexes was observed within 20 ns. Previous studies of the subject did not uncover this relationship. Regression model, coined FD model, was built to estimate binding free energies from binding site fractal dimension values. Leave-one-out cross-validation showed that our model reproduced accurately the absolute binding free energies for our training set (R 2  = 0.76; <|error|> =0.55 kcal/mol; SD error  = 0.19 kcal/mol). The fact that such a simple model may be applied raises some questions that are addressed in the article.
(Copyright © 2017 John Wiley & Sons, Ltd.)
Databáze: MEDLINE
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