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Improving Small-Molecule Force Field Parameters in Ligand Binding Studies

Small molecules are major players of many chemical processes in diverse fields, from material science to biology. They are made by a combination of carbon and heteroatoms typically organized in system-specific structures of different complexity. This peculiarity hampers the application of standard f...

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Autores principales: Raniolo, Stefano, Limongelli, Vittorio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8711133/
https://www.ncbi.nlm.nih.gov/pubmed/34966779
http://dx.doi.org/10.3389/fmolb.2021.760283
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author Raniolo, Stefano
Limongelli, Vittorio
author_facet Raniolo, Stefano
Limongelli, Vittorio
author_sort Raniolo, Stefano
collection PubMed
description Small molecules are major players of many chemical processes in diverse fields, from material science to biology. They are made by a combination of carbon and heteroatoms typically organized in system-specific structures of different complexity. This peculiarity hampers the application of standard force field parameters and their in silico study by means of atomistic simulations. Here, we combine quantum-mechanics and atomistic free-energy calculations to achieve an improved parametrization of the ligand torsion angles with respect to the state-of-the-art force fields in the paradigmatic molecular binding system benzamidine/trypsin. Funnel-Metadynamics calculations with the new parameters greatly reproduced the high-resolution crystallographic ligand binding mode and allowed a more accurate description of the binding mechanism, when the ligand might assume specific conformations to cross energy barriers. Our study impacts on future drug design investigations considering that the vast majority of marketed drugs are small-molecules.
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spelling pubmed-87111332021-12-28 Improving Small-Molecule Force Field Parameters in Ligand Binding Studies Raniolo, Stefano Limongelli, Vittorio Front Mol Biosci Molecular Biosciences Small molecules are major players of many chemical processes in diverse fields, from material science to biology. They are made by a combination of carbon and heteroatoms typically organized in system-specific structures of different complexity. This peculiarity hampers the application of standard force field parameters and their in silico study by means of atomistic simulations. Here, we combine quantum-mechanics and atomistic free-energy calculations to achieve an improved parametrization of the ligand torsion angles with respect to the state-of-the-art force fields in the paradigmatic molecular binding system benzamidine/trypsin. Funnel-Metadynamics calculations with the new parameters greatly reproduced the high-resolution crystallographic ligand binding mode and allowed a more accurate description of the binding mechanism, when the ligand might assume specific conformations to cross energy barriers. Our study impacts on future drug design investigations considering that the vast majority of marketed drugs are small-molecules. Frontiers Media S.A. 2021-12-13 /pmc/articles/PMC8711133/ /pubmed/34966779 http://dx.doi.org/10.3389/fmolb.2021.760283 Text en Copyright © 2021 Raniolo and Limongelli. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Raniolo, Stefano
Limongelli, Vittorio
Improving Small-Molecule Force Field Parameters in Ligand Binding Studies
title Improving Small-Molecule Force Field Parameters in Ligand Binding Studies
title_full Improving Small-Molecule Force Field Parameters in Ligand Binding Studies
title_fullStr Improving Small-Molecule Force Field Parameters in Ligand Binding Studies
title_full_unstemmed Improving Small-Molecule Force Field Parameters in Ligand Binding Studies
title_short Improving Small-Molecule Force Field Parameters in Ligand Binding Studies
title_sort improving small-molecule force field parameters in ligand binding studies
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8711133/
https://www.ncbi.nlm.nih.gov/pubmed/34966779
http://dx.doi.org/10.3389/fmolb.2021.760283
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