Advanced

Converging ligand-binding free energies obtained with free-energy perturbations at the quantum mechanical level

Olsson, Martin A. LU ; Söderhjelm, Pär LU and Ryde, Ulf LU (2016) In Journal of Computational Chemistry 37(17). p.1589-1600
Abstract

In this article, the convergence of quantum mechanical (QM) free-energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host, including the host, the ligand, and all water molecules within 4.5 Å of the ligand in the QM calculations (158-224 atoms). We use single-step exponential averaging (ssEA) and the non-Boltzmann Bennett acceptance ratio (NBB) methods to estimate QM/MM free energy with the semi-empirical PM6-DH2X method, both based on interaction energies. We show that ssEA with cumulant expansion gives a better convergence and uses half as many QM... (More)

In this article, the convergence of quantum mechanical (QM) free-energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host, including the host, the ligand, and all water molecules within 4.5 Å of the ligand in the QM calculations (158-224 atoms). We use single-step exponential averaging (ssEA) and the non-Boltzmann Bennett acceptance ratio (NBB) methods to estimate QM/MM free energy with the semi-empirical PM6-DH2X method, both based on interaction energies. We show that ssEA with cumulant expansion gives a better convergence and uses half as many QM calculations as NBB, although the two methods give consistent results. With 720,000 QM calculations per transformation, QM/MM free-energy estimates with a precision of 1 kJ/mol can be obtained for all eight relative energies with ssEA, showing that this approach can be used to calculate converged QM/MM binding free energies for realistic systems and large QM partitions.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
host-guest systems, ligand binding, non-Boltzmann Bennett acceptance ratio method, octa-acid host, QM/MM free-energy perturbation, quantum mechanics, semi-empirical methods, single-step exponential averaging
in
Journal of Computational Chemistry
volume
37
issue
17
pages
12 pages
publisher
John Wiley & Sons
external identifiers
  • Scopus:84964691709
ISSN
0192-8651
DOI
10.1002/jcc.24375
language
English
LU publication?
yes
id
d1df120d-6d0e-4d9a-9528-8a0ccd8d743b
date added to LUP
2016-09-27 12:18:55
date last changed
2016-10-13 05:14:24
@misc{d1df120d-6d0e-4d9a-9528-8a0ccd8d743b,
  abstract     = {<p>In this article, the convergence of quantum mechanical (QM) free-energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host, including the host, the ligand, and all water molecules within 4.5 Å of the ligand in the QM calculations (158-224 atoms). We use single-step exponential averaging (ssEA) and the non-Boltzmann Bennett acceptance ratio (NBB) methods to estimate QM/MM free energy with the semi-empirical PM6-DH2X method, both based on interaction energies. We show that ssEA with cumulant expansion gives a better convergence and uses half as many QM calculations as NBB, although the two methods give consistent results. With 720,000 QM calculations per transformation, QM/MM free-energy estimates with a precision of 1 kJ/mol can be obtained for all eight relative energies with ssEA, showing that this approach can be used to calculate converged QM/MM binding free energies for realistic systems and large QM partitions.</p>},
  author       = {Olsson, Martin A. and Söderhjelm, Pär and Ryde, Ulf},
  issn         = {0192-8651},
  keyword      = {host-guest systems,ligand binding,non-Boltzmann Bennett acceptance ratio method,octa-acid host,QM/MM free-energy perturbation,quantum mechanics,semi-empirical methods,single-step exponential averaging},
  language     = {eng},
  month        = {06},
  number       = {17},
  pages        = {1589--1600},
  publisher    = {ARRAY(0x9e54ae0)},
  series       = {Journal of Computational Chemistry},
  title        = {Converging ligand-binding free energies obtained with free-energy perturbations at the quantum mechanical level},
  url          = {http://dx.doi.org/10.1002/jcc.24375},
  volume       = {37},
  year         = {2016},
}