Molecular Dynamics Gives New Insights into the Glucose Tolerance and Inhibition Mechanisms on β-Glucosidases

Autor:	Johannes Kraml, Carlos H. da Silveira, Leon Sulfierry Corrêa Costa, Diego Mariano, Leonardo Henrique França de Lima, Klaus R. Liedl, Raquel C. de Melo-Minardi, Rafael E. O. Rocha
Rok vydání:	2019
Předmět:	glucose tolerance In silico Allosteric regulation Molecular Conformation Pharmaceutical Science Ligands 010402 general chemistry 01 natural sciences Article Substrate Specificity allosteric channel Analytical Chemistry lcsh:QD241-441 Structure-Activity Relationship 03 medical and health sciences Molecular dynamics lcsh:Organic chemistry Catalytic Domain β-Glucosidases Drug Discovery Amino Acids Physical and Theoretical Chemistry grid inhomogeneous solvation theory 030304 developmental biology 0303 health sciences GH1 biology Chemistry beta-Glucosidase Organic Chemistry Rational design Active site Energy landscape GH3 0104 chemical sciences Molecular Docking Simulation Kinetics free energy landscape Glucose molecular dynamics simulation Chemistry (miscellaneous) Product inhibition biology.protein Biophysics Molecular Medicine Poisson–Boltzmann surface area Glucosidases slingshot mechanism Protein Binding
Zdroj:	Molecules, Vol 24, Iss 18, p 3215 (2019) Molecules Volume 24 Issue 18
ISSN:	1420-3049
DOI:	10.3390/molecules24183215
Popis:	&beta Glucosidases are enzymes with high importance for many industrial processes, catalyzing the last and limiting step of the conversion of lignocellulosic material into fermentable sugars for biofuel production. However, &beta glucosidases are inhibited by high concentrations of the product (glucose), which limits the biofuel production on an industrial scale. For this reason, the structural mechanisms of tolerance to product inhibition have been the target of several studies. In this study, we performed in silico experiments, such as molecular dynamics (MD) simulations, free energy landscape (FEL) estimate, Poisson&ndash Boltzmann surface area (PBSA), and grid inhomogeneous solvation theory (GIST) seeking a better understanding of the glucose tolerance and inhibition mechanisms of a representative GH1 &beta glucosidase and a GH3 one. Our results suggest that the hydrophobic residues Y180, W350, and F349, as well the polar one D238 act in a mechanism for glucose releasing, herein called &ldquo slingshot mechanism&rdquo dependent also on an allosteric channel (AC). In addition, water activity modulation and the protein loop motions suggest that GH1 &beta Glucosidases present an active site more adapted to glucose withdrawal than GH3, in consonance with the GH1s lower product inhibition. The results presented here provide directions on the understanding of the molecular mechanisms governing inhibition and tolerance to the product in &beta glucosidases and can be useful for the rational design of optimized enzymes for industrial interests.
Databáze:	OpenAIRE
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