QMrebind: incorporating quantum mechanical force field reparameterization at the ligand binding site for improved drug-target kinetics through milestoning simulations.
Understanding the interaction of ligands with biomolecules is an integral component of drug discovery and development. Challenges for computing thermodynamic and kinetic quantities for pharmaceutically relevant receptor-ligand complexes include the size and flexibility of the ligands, large-scale co...
Main Authors: | , , |
---|---|
Format: | Article in Journal/Newspaper |
Language: | unknown |
Published: |
eScholarship, University of California
2023
|
Subjects: | |
Online Access: | https://escholarship.org/uc/item/97r2h4c5 |
id |
ftcdlib:oai:escholarship.org:ark:/13030/qt97r2h4c5 |
---|---|
record_format |
openpolar |
spelling |
ftcdlib:oai:escholarship.org:ark:/13030/qt97r2h4c5 2024-01-07T09:45:50+01:00 QMrebind: incorporating quantum mechanical force field reparameterization at the ligand binding site for improved drug-target kinetics through milestoning simulations. Votapka, Lane Amaro, Rommie Ojha, Anupam 2023-11-22 application/pdf https://escholarship.org/uc/item/97r2h4c5 unknown eScholarship, University of California qt97r2h4c5 https://escholarship.org/uc/item/97r2h4c5 public Chemical Science, vol 14, iss 45 article 2023 ftcdlib 2023-12-11T19:07:42Z Understanding the interaction of ligands with biomolecules is an integral component of drug discovery and development. Challenges for computing thermodynamic and kinetic quantities for pharmaceutically relevant receptor-ligand complexes include the size and flexibility of the ligands, large-scale conformational rearrangements of the receptor, accurate force field parameters, simulation efficiency, and sufficient sampling associated with rare events. Our recently developed multiscale milestoning simulation approach, SEEKR2 (Simulation Enabled Estimation of Kinetic Rates v.2), has demonstrated success in predicting unbinding (koff) kinetics by employing molecular dynamics (MD) simulations in regions closer to the binding site. The MD region is further subdivided into smaller Voronoi tessellations to improve the simulation efficiency and parallelization. To date, all MD simulations are run using general molecular mechanics (MM) force fields. The accuracy of calculations can be further improved by incorporating quantum mechanical (QM) methods into generating system-specific force fields through reparameterizing ligand partial charges in the bound state. The force field reparameterization process modifies the potential energy landscape of the bimolecular complex, enabling a more accurate representation of the intermolecular interactions and polarization effects at the bound state. We present QMrebind (Quantum Mechanical force field reparameterization at the receptor-ligand binding site), an ORCA-based software that facilitates reparameterizing the potential energy function within the phase space representing the bound state in a receptor-ligand complex. With SEEKR2 koff estimates and experimentally determined kinetic rates, we compare and interpret the receptor-ligand unbinding kinetics obtained using the newly reparameterized force fields for model host-guest systems and HSP90-inhibitor complexes. This method provides an opportunity to achieve higher accuracy in predicting receptor-ligand koff rate constants. Article in Journal/Newspaper Orca University of California: eScholarship |
institution |
Open Polar |
collection |
University of California: eScholarship |
op_collection_id |
ftcdlib |
language |
unknown |
description |
Understanding the interaction of ligands with biomolecules is an integral component of drug discovery and development. Challenges for computing thermodynamic and kinetic quantities for pharmaceutically relevant receptor-ligand complexes include the size and flexibility of the ligands, large-scale conformational rearrangements of the receptor, accurate force field parameters, simulation efficiency, and sufficient sampling associated with rare events. Our recently developed multiscale milestoning simulation approach, SEEKR2 (Simulation Enabled Estimation of Kinetic Rates v.2), has demonstrated success in predicting unbinding (koff) kinetics by employing molecular dynamics (MD) simulations in regions closer to the binding site. The MD region is further subdivided into smaller Voronoi tessellations to improve the simulation efficiency and parallelization. To date, all MD simulations are run using general molecular mechanics (MM) force fields. The accuracy of calculations can be further improved by incorporating quantum mechanical (QM) methods into generating system-specific force fields through reparameterizing ligand partial charges in the bound state. The force field reparameterization process modifies the potential energy landscape of the bimolecular complex, enabling a more accurate representation of the intermolecular interactions and polarization effects at the bound state. We present QMrebind (Quantum Mechanical force field reparameterization at the receptor-ligand binding site), an ORCA-based software that facilitates reparameterizing the potential energy function within the phase space representing the bound state in a receptor-ligand complex. With SEEKR2 koff estimates and experimentally determined kinetic rates, we compare and interpret the receptor-ligand unbinding kinetics obtained using the newly reparameterized force fields for model host-guest systems and HSP90-inhibitor complexes. This method provides an opportunity to achieve higher accuracy in predicting receptor-ligand koff rate constants. |
format |
Article in Journal/Newspaper |
author |
Votapka, Lane Amaro, Rommie Ojha, Anupam |
spellingShingle |
Votapka, Lane Amaro, Rommie Ojha, Anupam QMrebind: incorporating quantum mechanical force field reparameterization at the ligand binding site for improved drug-target kinetics through milestoning simulations. |
author_facet |
Votapka, Lane Amaro, Rommie Ojha, Anupam |
author_sort |
Votapka, Lane |
title |
QMrebind: incorporating quantum mechanical force field reparameterization at the ligand binding site for improved drug-target kinetics through milestoning simulations. |
title_short |
QMrebind: incorporating quantum mechanical force field reparameterization at the ligand binding site for improved drug-target kinetics through milestoning simulations. |
title_full |
QMrebind: incorporating quantum mechanical force field reparameterization at the ligand binding site for improved drug-target kinetics through milestoning simulations. |
title_fullStr |
QMrebind: incorporating quantum mechanical force field reparameterization at the ligand binding site for improved drug-target kinetics through milestoning simulations. |
title_full_unstemmed |
QMrebind: incorporating quantum mechanical force field reparameterization at the ligand binding site for improved drug-target kinetics through milestoning simulations. |
title_sort |
qmrebind: incorporating quantum mechanical force field reparameterization at the ligand binding site for improved drug-target kinetics through milestoning simulations. |
publisher |
eScholarship, University of California |
publishDate |
2023 |
url |
https://escholarship.org/uc/item/97r2h4c5 |
genre |
Orca |
genre_facet |
Orca |
op_source |
Chemical Science, vol 14, iss 45 |
op_relation |
qt97r2h4c5 https://escholarship.org/uc/item/97r2h4c5 |
op_rights |
public |
_version_ |
1787427466286989312 |