William L. Jorgensen

Comparison of simple potential functions for simulating liquid water

Classical Monte Carlo simulations have been carried out for liquid water in the NPT ensemble at 25 °C and 1 atm using six of the simpler intermolecular potential functions for the water dimer: Bernal–Fowler (BF), SPC, ST2, TIPS2, TIP3P, and TIP4P. Comparisons are made with experimental thermodynamic and structural data including the recent neutron diffraction results of Thiessen and Narten. The computed densities and potential energies are in reasonable accord with experiment except for the original BF model, which yields an 18% overestimate of the density and poor structural results. The TIPS2 and TIP4P potentials yield oxygen–oxygen partial structure functions in good agreement with the neutron diffraction results. The accord with the experimental OH and HH partial structure functions is poorer; however, the computed results for these functions are similar for all the potential functions. Consequently, the discrepancy may be due to the correction terms needed in processing the neutron data or to an effect uniformly neglected in the computations. Comparisons are also made for self‐diffusion coefficients obtained from molecular dynamics simulations. Overall, the SPC, ST2, TIPS2, and TIP4P models give reasonable structural and thermodynamic descriptions of liquid water and they should be useful in simulations of aqueous solutions. The simplicity of the SPC, TIPS2, and TIP4P functions is also attractive from a computational standpoint.

A five-site model for liquid water and the reproduction of the density anomaly by rigid, nonpolarizable potential functions

The ability of simple potential functions to reproduce accurately the density of liquid water from −37 to 100 °C at 1 to 10 000 atm has been further explored. The result is the five-site TIP5P model, which yields significantly improved results; the average error in the density over the 100° temperature range from −37.5 to 62.5 °C at 1 atm is only 0.006 g cm−3. Classical Monte Carlo statistical mechanics calculations have been performed to optimize the parameters, especially the position of the negative charges along the lone-pair directions. Initial calculations with 216 molecules in the NPT ensemble at 1 atm focused on finding a model that reproduced the shape of the liquid density curve as a function of temperature. Calculations performed for 512 molecules with the final TIP5P model demonstrate that the density maximum near 4 °C at 1 atm is reproduced, while high-quality structural and thermodynamic results are maintained. Attainment of high precision for the low-temperature runs required sampling for m...

Temperature and size dependence for Monte Carlo simulations of TIP4P water

A series of Monte Carlo simulations has been carried out to characterize the temperature and size dependence of the results for liquid water using the TIP4P potential function. Five temperatures from -25 to 100°C and four system sizes from 64 to 512 molecules have been studied. Comparisons are made with experimental thermodynamic and structural data as well as results of prior simulations.

Monte Carlo simulation of differences in free energies of hydration

Perturbation theory has been applied to calculate the relative free energies of hydration of methanol and ethane in dilute soluton. It is demonstrated that only two or three Monte Carlo simulations using double‐wide sampling are necessary to obtain results with high precision. The small statistical uncertainty in the computed change in free energy of hydration and the good accord with experimental thermodynamic data are most encouraging for application of the procedure to a wide range of problems. Structural effects accompanying the mutation of methanol to ethane in water are also discussed; hydrogen bonding to the solute is essentialy eliminated by only a 25% reduction in the atomic charges of methanol.

Revised TIPS for simulations of liquid water and aqueous solutions

An intermolecular potential function for the water dimer (TIPS2) has been developed and used in Monte Carlo simulations of liquid water in the NPT ensemble at 1 atm and −30, 25, and 75 °C. A simple four‐site model is employed for the monomers with one Lennard‐Jones term acting between oxygens and Coulomb terms for the intermolecular interactions between the charged sites. The function yields excellent thermodynamic results for the liquid across the temperature range; the average error in the computed densities and energies is 1.2% and a temperature of maximum density is indicated in the vicinity of 25 °C. Futhermore, the structural results are in reasonable agreement with Narten’s x‐ray data. Specifically, the oxygen–oxygen radial distribution function shows three well‐resolved peaks at 25 °C and a reduction in structure with increasing temperature. The simplicity of the TIPS2 potential,its success in describing liquid water, and the availability of TIPS parameters for hydrocarbons and for various organic functional groups provide a framework for computer simulations of aqueous solutions.

OPLS all‐atom force field for carbohydrates

The OPLS all‐atom (AA) force field for organic and biomolecular systems has been expanded to include carbohydrates. Starting with reported nonbonded parameters of alcohols, ethers, and diols, torsional parameters were fit to reproduce results from ab initio calculations on the hexopyranoses, α,β‐d‐glucopyranose, α,β‐d‐mannopyranose, α,β‐d‐galactopyranose, methyl α,β‐d‐glucopyranoside, and methyl α,β‐d‐mannopyranoside. In all, geometry optimizations were carried out for 144 conformers at the restricted Hartree–Fock (RHF)/6–31G* level. For the conformers with a relative energy within 3 kcal/mol of the global minima, the effects of electron correlation and basis‐set extension were considered by performing single‐point calculations with density functional theory at the B3LYP/6–311+G** level. The torsional parameters for the OPLS‐AA force field were parameterized to reproduce the energies and structures of these 44 conformers. The resultant force field reproduces the ab initio calculated energies with an average unsigned error of 0.41 kcal/mol. The α/β ratios as well as the relative energies between the isomeric hexopyranoses are in good accord with the ab initio results. The predictive abilities of the force field were also tested against RHF/6–31G* results for d‐allopyranose with excellent success; a surprising discovery is that the lowest energy conformer of d‐allopyranose is a β anomer. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1955–1970, 1997

Prediction of drug solubility from structure.

The aqueous solubility of a drug is an important factor affecting its bioavailability. Numerous computational methods have been developed for the prediction of aqueous solubility from a compounds structure. A review is provided of the methodology and quality of results for the most useful procedures including the model implemented in the QikProp program. Viable methods now exist for predictions with less than 1 log unit uncertainty, which is adequate for prescreening synthetic candidates or design of combinatorial libraries. Further progress with predictive methods would require an experimental database of highly accurate solubilities for a large, diverse collection of drug-like molecules.

OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins

The parametrization and validation of the OPLS3 force field for small molecules and proteins are reported. Enhancements with respect to the previous version (OPLS2.1) include the addition of off-atom charge sites to represent halogen bonding and aryl nitrogen lone pairs as well as a complete refit of peptide dihedral parameters to better model the native structure of proteins. To adequately cover medicinal chemical space, OPLS3 employs over an order of magnitude more reference data and associated parameter types relative to other commonly used small molecule force fields (e.g., MMFF and OPLS_2005). As a consequence, OPLS3 achieves a high level of accuracy across performance benchmarks that assess small molecule conformational propensities and solvation. The newly fitted peptide dihedrals lead to significant improvements in the representation of secondary structure elements in simulated peptides and native structure stability over a number of proteins. Together, the improvements made to both the small molecule and protein force field lead to a high level of accuracy in predicting protein-ligand binding measured over a wide range of targets and ligands (less than 1 kcal/mol RMS error) representing a 30% improvement over earlier variants of the OPLS force field.

Efficient drug lead discovery and optimization.

During the 1980s, advances in the abilities to perform computer simulations of chemical and biomolecular systems and to calculate free energy changes led to the expectation that such methodology would soon show great utility for guiding molecular design. Important potential applications included design of selective receptors, catalysts, and regulators of biological function including enzyme inhibitors. This time also saw the rise of high-throughput screening and combinatorial chemistry along with complementary computational methods for de novo design and virtual screening including docking. These technologies appeared poised to deliver diverse lead compounds for any biological target. As with many technological advances, realization of the expectations required significant additional effort and time. However, as summarized here, striking success has now been achieved for computer-aided drug lead generation and optimization. De novo design using both molecular growing and docking are illustrated for lead generation, and lead optimization features free energy perturbation calculations in conjunction with Monte Carlo statistical mechanics simulations for protein-inhibitor complexes in aqueous solution. The specific applications are to the discovery of non-nucleoside inhibitors of HIV reverse transcriptase (HIV-RT) and inhibitors of the binding of the proinflammatory cytokine MIF to its receptor CD74. A standard protocol is presented that includes scans for possible additions of small substituents to a molecular core, interchange of heterocycles, and focused optimization of substituents at one site. Initial leads with activities at low-micromolar concentrations have been advanced rapidly to low-nanomolar inhibitors.

Performance of B3LYP Density Functional Methods for a Large Set of Organic Molecules

Testing of the commonly used hybrid density functional B3LYP with the 6-31G(d), 6-31G(d,p), and 6-31+G(d,p) basis sets has been carried out for 622 neutral, closed-shell organic compounds containing the elements C, H, N, and O. The focus is comparison of computed and experimental heats of formation and isomerization energies. In addition, the effect of an empirical dispersion correction term has been evaluated and found to improve agreement with the experimental data. For the 622 compounds, the mean absolute errors (MAE) in the heats of formation are 3.1, 2.6, 2.7, and 2.4 kcal/mol for B3LYP/6-31G(d), B3LYP/6-31G(d,p), B3LYP/6-31+G(d,p), and B3LYP/6-31+G(d,p) with the dispersion correction. A diverse set of 34 isomerizations highlights specific issues of general interest, such as performance on differences in steric effects, conjugation, and bonding. The corresponding MAEs for the isomerizations are 2.7, 2.4, 2.2, and 1.9 kcal/mol. Improvement is obtained for isomerizations of amines and alcohols when both polarization and diffuse functions are used, but the overstabilization of linear alkanes compared to branched isomers can be relieved only with the dispersion correction. Besides the insights on DFT methods, the study also aimed to quantify the gains in accuracy that can be achieved by replacing energetics from NDO-based semiempirical methods with DFT results. Since the MAEs obtained with the PDDG/PM3 method for the 622 heats of formation and 34 isomerizations are 2.8 and 2.3 kcal/mol, negligible advantage in accuracy for the B3LYP-based methods emerged in the absence of the dispersion corrections.