TY - JOUR
T1 - Prediction of hydration free energies for aliphatic and aromatic chloro derivatives using molecular dynamics simulations with the OPLS-AA force field
AU - Beckstein, Oliver
AU - Iorga, Bogdan I.
N1 - Funding Information:
Acknowledgments This work was carried out, in part, under the HPC-EUROPA2 project (project number: 228398) with the support of the European Commission Capacities Area-Research Infrastructures Initiative.
PY - 2012/5
Y1 - 2012/5
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.
KW - Free energy perturbation
KW - Hydration free energy
KW - Ligand parameterization
KW - Molecular dynamics
KW - OPLS-AA force field
KW - Thermodynamic integration
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U2 - 10.1007/s10822-011-9527-9
DO - 10.1007/s10822-011-9527-9
M3 - Article
C2 - 22187140
AN - SCOPUS:84863114434
SN - 0920-654X
VL - 26
SP - 635
EP - 645
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
IS - 5
ER -