Thermostabilizing mechanisms of canonical single amino acid substitutions at a GH1 β-glucosidase probed by multiple MD and computational approaches
Rafael Eduardo Oliveira Rocha
Laboratory of Molecular Modelling and Bioinformatics (LAMMB), Department of Physical and Biological Sciences, Campus Sete Lagoas, Universidade Federal de São João Del Rei, Sete Lagoas, Brazil
Laboratory of Bioinformatics and Systems (LBS), Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Laboratory of Molecular Modeling and Drug Design, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Search for more papers by this authorDiego César Batista Mariano
Laboratory of Bioinformatics and Systems (LBS), Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Search for more papers by this authorTiago Silva Almeida
Laboratory of Molecular Modelling and Bioinformatics (LAMMB), Department of Physical and Biological Sciences, Campus Sete Lagoas, Universidade Federal de São João Del Rei, Sete Lagoas, Brazil
Search for more papers by this authorLeon Sulfierry CorrêaCosta
Laboratory of Molecular Modelling and Bioinformatics (LAMMB), Department of Physical and Biological Sciences, Campus Sete Lagoas, Universidade Federal de São João Del Rei, Sete Lagoas, Brazil
Computational Modeling Coordination (COMOD), Laboratório Nacional de Computação Científica (LNCC), Petrópolis, Brazil
Search for more papers by this authorPedro Henrique Camargo Fischer
Laboratory of Molecular Modelling and Bioinformatics (LAMMB), Department of Physical and Biological Sciences, Campus Sete Lagoas, Universidade Federal de São João Del Rei, Sete Lagoas, Brazil
Search for more papers by this authorLucianna Helene Santos
Laboratory of Bioinformatics and Systems (LBS), Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Laboratory of Molecular Modeling and Drug Design, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Search for more papers by this authorErnesto Raul Caffarena
Scientific Computing Program, Fiocruz, Rio de Janeiro, Brazil
Search for more papers by this authorCarlos Henrique da Silveira
Technological Sciences Institute, Universidade Federal de Itajubá, Itabira, Minas Gerais, Brazil
Search for more papers by this authorLeonida M. Lamp
Institute of General, Inorganic and Theoretical Chemistry, and Center for Chemistry and Biomedicine Innsbruck (CCB), University of Innsbruck, Innsbruck, Austria
Search for more papers by this authorMonica Lisa Fernandez-Quintero
Institute of General, Inorganic and Theoretical Chemistry, and Center for Chemistry and Biomedicine Innsbruck (CCB), University of Innsbruck, Innsbruck, Austria
Search for more papers by this authorKlaus Roman Liedl
Institute of General, Inorganic and Theoretical Chemistry, and Center for Chemistry and Biomedicine Innsbruck (CCB), University of Innsbruck, Innsbruck, Austria
Search for more papers by this authorRaquel Cardoso de Melo-Minardi
Laboratory of Bioinformatics and Systems (LBS), Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Search for more papers by this authorCorresponding Author
Leonardo Henrique França de Lima
Laboratory of Molecular Modelling and Bioinformatics (LAMMB), Department of Physical and Biological Sciences, Campus Sete Lagoas, Universidade Federal de São João Del Rei, Sete Lagoas, Brazil
Institute of General, Inorganic and Theoretical Chemistry, and Center for Chemistry and Biomedicine Innsbruck (CCB), University of Innsbruck, Innsbruck, Austria
Correspondence
Leonardo Henrique França de Lima, Laboratory of Molecular Modelling and Bioinformatics (LAMMB), Department of Physical and Biological Sciences, Campus Sete Lagoas, Universidade Federal de São João Del Rei, 35701-970 SeteLagoas - MG, Brazil.
Email: [email protected]
Search for more papers by this authorRafael Eduardo Oliveira Rocha
Laboratory of Molecular Modelling and Bioinformatics (LAMMB), Department of Physical and Biological Sciences, Campus Sete Lagoas, Universidade Federal de São João Del Rei, Sete Lagoas, Brazil
Laboratory of Bioinformatics and Systems (LBS), Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Laboratory of Molecular Modeling and Drug Design, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Search for more papers by this authorDiego César Batista Mariano
Laboratory of Bioinformatics and Systems (LBS), Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Search for more papers by this authorTiago Silva Almeida
Laboratory of Molecular Modelling and Bioinformatics (LAMMB), Department of Physical and Biological Sciences, Campus Sete Lagoas, Universidade Federal de São João Del Rei, Sete Lagoas, Brazil
Search for more papers by this authorLeon Sulfierry CorrêaCosta
Laboratory of Molecular Modelling and Bioinformatics (LAMMB), Department of Physical and Biological Sciences, Campus Sete Lagoas, Universidade Federal de São João Del Rei, Sete Lagoas, Brazil
Computational Modeling Coordination (COMOD), Laboratório Nacional de Computação Científica (LNCC), Petrópolis, Brazil
Search for more papers by this authorPedro Henrique Camargo Fischer
Laboratory of Molecular Modelling and Bioinformatics (LAMMB), Department of Physical and Biological Sciences, Campus Sete Lagoas, Universidade Federal de São João Del Rei, Sete Lagoas, Brazil
Search for more papers by this authorLucianna Helene Santos
Laboratory of Bioinformatics and Systems (LBS), Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Laboratory of Molecular Modeling and Drug Design, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
Search for more papers by this authorErnesto Raul Caffarena
Scientific Computing Program, Fiocruz, Rio de Janeiro, Brazil
Search for more papers by this authorCarlos Henrique da Silveira
Technological Sciences Institute, Universidade Federal de Itajubá, Itabira, Minas Gerais, Brazil
Search for more papers by this authorLeonida M. Lamp
Institute of General, Inorganic and Theoretical Chemistry, and Center for Chemistry and Biomedicine Innsbruck (CCB), University of Innsbruck, Innsbruck, Austria
Search for more papers by this authorMonica Lisa Fernandez-Quintero
Institute of General, Inorganic and Theoretical Chemistry, and Center for Chemistry and Biomedicine Innsbruck (CCB), University of Innsbruck, Innsbruck, Austria
Search for more papers by this authorKlaus Roman Liedl
Institute of General, Inorganic and Theoretical Chemistry, and Center for Chemistry and Biomedicine Innsbruck (CCB), University of Innsbruck, Innsbruck, Austria
Search for more papers by this authorRaquel Cardoso de Melo-Minardi
Laboratory of Bioinformatics and Systems (LBS), Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Search for more papers by this authorCorresponding Author
Leonardo Henrique França de Lima
Laboratory of Molecular Modelling and Bioinformatics (LAMMB), Department of Physical and Biological Sciences, Campus Sete Lagoas, Universidade Federal de São João Del Rei, Sete Lagoas, Brazil
Institute of General, Inorganic and Theoretical Chemistry, and Center for Chemistry and Biomedicine Innsbruck (CCB), University of Innsbruck, Innsbruck, Austria
Correspondence
Leonardo Henrique França de Lima, Laboratory of Molecular Modelling and Bioinformatics (LAMMB), Department of Physical and Biological Sciences, Campus Sete Lagoas, Universidade Federal de São João Del Rei, 35701-970 SeteLagoas - MG, Brazil.
Email: [email protected]
Search for more papers by this authorRafael Eduardo Oliveira Rocha and Diego César Batista Mariano contributed equally to this work.
Funding information: Conselho Nacional de Desenvolvimento Científico e Tecnológico; Fundação de Amparo à Pesquisa do Estado de Minas Gerais; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Abstract
β-glucosidases play a pivotal role in second-generation biofuel (2G-biofuel) production. For this application, thermostable enzymes are essential due to the denaturing conditions on the bioreactors. Random amino acid substitutions have originated new thermostable β-glucosidases, but without a clear understanding of their molecular mechanisms. Here, we probe by different molecular dynamics simulation approaches with distinct force fields and submitting the results to various computational analyses, the molecular bases of the thermostabilization of the Paenibacillus polymyxa GH1 β-glucosidase by two-point mutations E96K (TR1) and M416I (TR2). Equilibrium molecular dynamic simulations (eMD) at different temperatures, principal component analysis (PCA), virtual docking, metadynamics (MetaDy), accelerated molecular dynamics (aMD), Poisson-Boltzmann surface analysis, grid inhomogeneous solvation theory and colony method estimation of conformational entropy allow to converge to the idea that the stabilization carried by both substitutions depend on different contributions of three classic mechanisms: (i) electrostatic surface stabilization; (ii) efficient isolation of the hydrophobic core from the solvent, with energetic advantages at the solvation cap; (iii) higher distribution of the protein dynamics at the mobile active site loops than at the protein core, with functional and entropic advantages. Mechanisms i and ii predominate for TR1, while in TR2, mechanism iii is dominant. Loop A integrity and loops A, C, D, and E dynamics play critical roles in such mechanisms. Comparison of the dynamic and topological changes observed between the thermostable mutants and the wildtype protein with amino acid co-evolutive networks and thermostabilizing hotspots from the literature allow inferring that the mechanisms here recovered can be related to the thermostability obtained by different substitutions along the whole family GH1. We hope the results and insights discussed here can be helpful for future rational approaches to the engineering of optimized β-glucosidases for 2G-biofuel production for industry, biotechnology, and science.
CONFLICT OF INTERESTS
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings were of this study derived from the following resources available in the public domain: https://www.rcsb.org/structure/5IDI, https://www.rcsb.org/structure/4MDO, https://www.rcsb.org/structure/4PTX
Supporting Information
| Filename | Description |
|---|---|
| prot26424-sup-0001-Supinfo.docxWord 2007 document , 1.3 MB | Appendix S1 Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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