Prediction of hydration free energies for aliphatic and aromatic chloro derivatives using molecular dynamics simulations with the OPLS-AA force field

Oliver Beckstein, Bogdan I. Iorga

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17 Citations (Scopus)

Abstract

All-atom molecular dynamics computer simulations were used to blindly predict the hydration free energies of a range of chloro-organic compounds as part of the SAMPL3 challenge. All compounds were parameterized within the framework of the OPLS-AA force field, using an established protocol to compute the absolute hydration free energy via a windowed free energy perturbation approach and thermodynamic integration. Three different approaches to deriving partial charge parameters were pursued: (1) using existing OPLS-AA atom types and charges with minor adjustments of partial charges on equivalent connecting atoms; (2) calculation of quantum mechanical charges via geometry optimization, followed by electrostatic potential (ESP) fitting, using Jaguar at the LMP2/cc-pVTZ(-F) level; and (3) via geometry optimization and CHelpG charges (Gaussian03 at the HF/6-31G* level), followed by two-stage RESP fitting. Protocol 3 generated the most accurate predictions with a root mean square (RMS) error of 1.2 kcal mol-1 for the entire data set. It was found that the deficiency of the standard OPLS-AA parameters, protocol 1 (RMS error 2.4 kcal moL-1 overall), was mostly due to compounds with more than three chlorine substituents on an aromatic ring. For this latter subset, the RMS errors were 1.4 kcal mol-1 (protocol 3) and 4.3 kcal moL -1 (protocol 1), respectively. We propose new OPLS-AA atom types for aromatic carbon and chlorine atoms in rings with ≥4 Cl-substituents that perform better than the best QM-based approach, resulting in an RMS error of 1.2 kcal mol-1 for these difficult compounds.

Original languageEnglish (US)
Pages (from-to)635-645
Number of pages11
JournalJournal of Computer-Aided Molecular Design
Volume26
Issue number5
DOIs
StatePublished - May 2012

Fingerprint

Chlorine
Molecular Dynamics Simulation
Hydration
root-mean-square errors
field theory (physics)
Free energy
hydration
Molecular dynamics
Mean square error
free energy
Molecular Computers
molecular dynamics
Derivatives
Atoms
Computer simulation
predictions
Static Electricity
Thermodynamics
Computer Simulation
atoms

Keywords

  • Free energy perturbation
  • Hydration free energy
  • Ligand parameterization
  • Molecular dynamics
  • OPLS-AA force field
  • Thermodynamic integration

ASJC Scopus subject areas

  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Computer Science Applications

Cite this

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title = "Prediction of hydration free energies for aliphatic and aromatic chloro derivatives using molecular dynamics simulations with the OPLS-AA force field",
abstract = "All-atom molecular dynamics computer simulations were used to blindly predict the hydration free energies of a range of chloro-organic compounds as part of the SAMPL3 challenge. All compounds were parameterized within the framework of the OPLS-AA force field, using an established protocol to compute the absolute hydration free energy via a windowed free energy perturbation approach and thermodynamic integration. Three different approaches to deriving partial charge parameters were pursued: (1) using existing OPLS-AA atom types and charges with minor adjustments of partial charges on equivalent connecting atoms; (2) calculation of quantum mechanical charges via geometry optimization, followed by electrostatic potential (ESP) fitting, using Jaguar at the LMP2/cc-pVTZ(-F) level; and (3) via geometry optimization and CHelpG charges (Gaussian03 at the HF/6-31G* level), followed by two-stage RESP fitting. Protocol 3 generated the most accurate predictions with a root mean square (RMS) error of 1.2 kcal mol-1 for the entire data set. It was found that the deficiency of the standard OPLS-AA parameters, protocol 1 (RMS error 2.4 kcal moL-1 overall), was mostly due to compounds with more than three chlorine substituents on an aromatic ring. For this latter subset, the RMS errors were 1.4 kcal mol-1 (protocol 3) and 4.3 kcal moL -1 (protocol 1), respectively. We propose new OPLS-AA atom types for aromatic carbon and chlorine atoms in rings with ≥4 Cl-substituents that perform better than the best QM-based approach, resulting in an RMS error of 1.2 kcal mol-1 for these difficult compounds.",
keywords = "Free energy perturbation, Hydration free energy, Ligand parameterization, Molecular dynamics, OPLS-AA force field, Thermodynamic integration",
author = "Oliver Beckstein and Iorga, {Bogdan I.}",
year = "2012",
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T1 - Prediction of hydration free energies for aliphatic and aromatic chloro derivatives using molecular dynamics simulations with the OPLS-AA force field

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AU - Iorga, Bogdan I.

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N2 - All-atom molecular dynamics computer simulations were used to blindly predict the hydration free energies of a range of chloro-organic compounds as part of the SAMPL3 challenge. All compounds were parameterized within the framework of the OPLS-AA force field, using an established protocol to compute the absolute hydration free energy via a windowed free energy perturbation approach and thermodynamic integration. Three different approaches to deriving partial charge parameters were pursued: (1) using existing OPLS-AA atom types and charges with minor adjustments of partial charges on equivalent connecting atoms; (2) calculation of quantum mechanical charges via geometry optimization, followed by electrostatic potential (ESP) fitting, using Jaguar at the LMP2/cc-pVTZ(-F) level; and (3) via geometry optimization and CHelpG charges (Gaussian03 at the HF/6-31G* level), followed by two-stage RESP fitting. Protocol 3 generated the most accurate predictions with a root mean square (RMS) error of 1.2 kcal mol-1 for the entire data set. It was found that the deficiency of the standard OPLS-AA parameters, protocol 1 (RMS error 2.4 kcal moL-1 overall), was mostly due to compounds with more than three chlorine substituents on an aromatic ring. For this latter subset, the RMS errors were 1.4 kcal mol-1 (protocol 3) and 4.3 kcal moL -1 (protocol 1), respectively. We propose new OPLS-AA atom types for aromatic carbon and chlorine atoms in rings with ≥4 Cl-substituents that perform better than the best QM-based approach, resulting in an RMS error of 1.2 kcal mol-1 for these difficult compounds.

AB - All-atom molecular dynamics computer simulations were used to blindly predict the hydration free energies of a range of chloro-organic compounds as part of the SAMPL3 challenge. All compounds were parameterized within the framework of the OPLS-AA force field, using an established protocol to compute the absolute hydration free energy via a windowed free energy perturbation approach and thermodynamic integration. Three different approaches to deriving partial charge parameters were pursued: (1) using existing OPLS-AA atom types and charges with minor adjustments of partial charges on equivalent connecting atoms; (2) calculation of quantum mechanical charges via geometry optimization, followed by electrostatic potential (ESP) fitting, using Jaguar at the LMP2/cc-pVTZ(-F) level; and (3) via geometry optimization and CHelpG charges (Gaussian03 at the HF/6-31G* level), followed by two-stage RESP fitting. Protocol 3 generated the most accurate predictions with a root mean square (RMS) error of 1.2 kcal mol-1 for the entire data set. It was found that the deficiency of the standard OPLS-AA parameters, protocol 1 (RMS error 2.4 kcal moL-1 overall), was mostly due to compounds with more than three chlorine substituents on an aromatic ring. For this latter subset, the RMS errors were 1.4 kcal mol-1 (protocol 3) and 4.3 kcal moL -1 (protocol 1), respectively. We propose new OPLS-AA atom types for aromatic carbon and chlorine atoms in rings with ≥4 Cl-substituents that perform better than the best QM-based approach, resulting in an RMS error of 1.2 kcal mol-1 for these difficult compounds.

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