John Shelley | Schrodinger - Academia.edu (original) (raw)
Papers by John Shelley
Journal of Chemical Theory and Computation, 2013
Accurate and reliable calculation of protein−ligand binding affinities remains a hotbed of comput... more Accurate and reliable calculation of protein−ligand binding affinities remains a hotbed of computer-aided drug design research. Despite the potentially large impact FEP (free energy perturbation) may have in drug design projects, practical applications of FEP in industrial contexts have been limited. In this work, we use a recently developed method, FEP/REST (free energy perturbation/replica exchange with solute tempering), to calculate the relative binding affinities for a set of congeneric ligands binding to the CDK2 receptor. We compare the FEP/REST results with traditional FEP/MD (molecular dynamics) results and MM/GBSA (molecular mechanics/ Generalized Born Surface Area model) results and examine why FEP/REST performed notably better than these other methods, as well as why certain ligand mutations lead to large increases of the binding affinity while others do not. We also introduce a mathematical framework for assessing the consistency and reliability of the calculations using cycle closures in FEP mutation paths.
Molecular Physics, Dec 3, 2010
In computer simulations of water between hydrophobic walls the results exhibit a strong dependenc... more In computer simulations of water between hydrophobic walls the results exhibit a strong dependence upon the boundary conditions applied. With the minimum image (MI) convention the water molecules tend to be orientationally ordered throughout the simulation cell (Valleau, J. P., and Gardner, A. A., 1987, J. chem. Phys., 86, 4162) whereas, if a spherical cut-off (SC) is applied, strong orientational order is found only in the immediate vicinity of the surface (Lee, C. Y., McCammon, J. A., and Rossky, P. J., 1984, J. chem. Phys., 80, 4448). These conflicting observations have remained unresolved, and clearly raise troubling questions concerning the validity of simulation results for water between surfaces of all types. In the present paper we explore this problem by carrying out a detailed analysis of the results obtained with various types of boundary condition. These include Ewald calculations carried out with a central simulation cell adapted to describe the slab geometry of interest. It is shown that the order observed in MI calculations is an artefact of that particular truncation. The reason for this is isolated and discussed. Similar problems are found if a cylindrical cut-off is employed. The Ewald and SC methods gave qualitatively similar results for systems similar to those considered in previous simulations. However, for some geometries problems can also arise with the SC method. We conclude that in general the slab-adapted Ewald method is the safest choice.
Langmuir, 2000
A classical molecular dynamics simulation of a monolayer of sodium laurate (dodecanoate) at the a... more A classical molecular dynamics simulation of a monolayer of sodium laurate (dodecanoate) at the airwater interface has been carried out. We found highly curved, dynamic structural features within the soap monolayer during the simulation. Introduction of salt in the water appears to suppress the formation of these structural patterns, indicating that electrostatic repulsion among anionic headgroups is a key component in creating these structures.
Surfactants in Solution, 1991
Reviews in Computational Chemistry, 1998
Physical Review A, 1986
Well-resolved Ramsey fringes have been demonstrated using laser Stark spectroscopy of CH3F in a m... more Well-resolved Ramsey fringes have been demonstrated using laser Stark spectroscopy of CH3F in a molecular beam with two interaction regions. Fringe separations as low as 155 kHz were obtained. The interaction regions were produced by masks containing slits placed in the Gaussian-profile beam of a cw CO2 laser. Population inversion resulting from a frequency sweep associated with the curvature of
Molecular Physics, 1996
In computer simulations of water between hydrophobic walls the results exhibit a strong dependenc... more In computer simulations of water between hydrophobic walls the results exhibit a strong dependence upon the boundary conditions applied. With the minimum image (MI) convention the water molecules tend to be orientationally ordered throughout the simulation cell (Valleau, J. P., and Gardner, A. A., 1987, J. chem. Phys., 86, 4162) whereas, if a spherical cut-off (SC) is applied, strong orientational order is found only in the immediate vicinity of the surface (Lee, C. Y., McCammon, J. A., and Rossky, P. J., 1984, J. chem. Phys., 80, 4448). These conflicting observations have remained unresolved, and clearly raise troubling questions concerning the validity of simulation results for water between surfaces of all types. In the present paper we explore this problem by carrying out a detailed analysis of the results obtained with various types of boundary condition. These include Ewald calculations carried out with a central simulation cell adapted to describe the slab geometry of interest. It is shown that the order observed in MI calculations is an artefact of that particular truncation. The reason for this is isolated and discussed. Similar problems are found if a cylindrical cut-off is employed. The Ewald and SC methods gave qualitatively similar results for systems similar to those considered in previous simulations. However, for some geometries problems can also arise with the SC method. We conclude that in general the slab-adapted Ewald method is the safest choice.
Langmuir, 2000
A classical molecular dynamics simulation of a monolayer of sodium laurate (dodecanoate) at the a... more A classical molecular dynamics simulation of a monolayer of sodium laurate (dodecanoate) at the airwater interface has been carried out. We found highly curved, dynamic structural features within the soap monolayer during the simulation. Introduction of salt in the water appears to suppress the formation of these structural patterns, indicating that electrostatic repulsion among anionic headgroups is a key component in creating these structures.
The Journal of Chemical Physics, 1995
The Journal of Chemical Physics, 1994
The Journal of Chemical Physics, 1999
ABSTRACT Grand canonical Monte Carlo calculations are used to investigate the demixing transition... more ABSTRACT Grand canonical Monte Carlo calculations are used to investigate the demixing transition in model ionic solutions where the solvent is explicitly included. Charged hard sphere ions in hard sphere, dipolar hard sphere and quadrupolar hard sphere solvents are considered and the results are compared with the primitive (continuum solvent) model. For all solvents considered, it is found that the demixing transition is in the same general region of the phase diagram and is roughly described by liquid-vapor equilibrium in the primitive model. However, details such as the precise location of the critical point and the width of the unstable region depend upon the exact nature of the solvent. © 1999 American Institute of Physics.
The Journal of Chemical Physics, 1997
The modeling and nature of the physisorption of water at the metal (Hg)-water interface is explor... more The modeling and nature of the physisorption of water at the metal (Hg)-water interface is explored in this paper. We have evaluated potential models that fit into three general classes that are employed in the literature. These classes are distinguished by the manner in which the isotropic interactions between the metal and the water are modeled: namely, as non-attractive, weakly
The Journal of Chemical Physics, 1995
Current Opinion in Colloid & Interface Science, 2000
Major advances have been made at several levels of computer simulation of surfactant solutions. A... more Major advances have been made at several levels of computer simulation of surfactant solutions. Atomistic level studies of preassembled surfactant structures have become fairly routine. The development of structure in surfactant solutions has now been studied using ...
Journal of Chemical Theory and Computation, 2013
Accurate and reliable calculation of protein−ligand binding affinities remains a hotbed of comput... more Accurate and reliable calculation of protein−ligand binding affinities remains a hotbed of computer-aided drug design research. Despite the potentially large impact FEP (free energy perturbation) may have in drug design projects, practical applications of FEP in industrial contexts have been limited. In this work, we use a recently developed method, FEP/REST (free energy perturbation/replica exchange with solute tempering), to calculate the relative binding affinities for a set of congeneric ligands binding to the CDK2 receptor. We compare the FEP/REST results with traditional FEP/MD (molecular dynamics) results and MM/GBSA (molecular mechanics/ Generalized Born Surface Area model) results and examine why FEP/REST performed notably better than these other methods, as well as why certain ligand mutations lead to large increases of the binding affinity while others do not. We also introduce a mathematical framework for assessing the consistency and reliability of the calculations using cycle closures in FEP mutation paths.
Molecular Physics, Dec 3, 2010
In computer simulations of water between hydrophobic walls the results exhibit a strong dependenc... more In computer simulations of water between hydrophobic walls the results exhibit a strong dependence upon the boundary conditions applied. With the minimum image (MI) convention the water molecules tend to be orientationally ordered throughout the simulation cell (Valleau, J. P., and Gardner, A. A., 1987, J. chem. Phys., 86, 4162) whereas, if a spherical cut-off (SC) is applied, strong orientational order is found only in the immediate vicinity of the surface (Lee, C. Y., McCammon, J. A., and Rossky, P. J., 1984, J. chem. Phys., 80, 4448). These conflicting observations have remained unresolved, and clearly raise troubling questions concerning the validity of simulation results for water between surfaces of all types. In the present paper we explore this problem by carrying out a detailed analysis of the results obtained with various types of boundary condition. These include Ewald calculations carried out with a central simulation cell adapted to describe the slab geometry of interest. It is shown that the order observed in MI calculations is an artefact of that particular truncation. The reason for this is isolated and discussed. Similar problems are found if a cylindrical cut-off is employed. The Ewald and SC methods gave qualitatively similar results for systems similar to those considered in previous simulations. However, for some geometries problems can also arise with the SC method. We conclude that in general the slab-adapted Ewald method is the safest choice.
Langmuir, 2000
A classical molecular dynamics simulation of a monolayer of sodium laurate (dodecanoate) at the a... more A classical molecular dynamics simulation of a monolayer of sodium laurate (dodecanoate) at the airwater interface has been carried out. We found highly curved, dynamic structural features within the soap monolayer during the simulation. Introduction of salt in the water appears to suppress the formation of these structural patterns, indicating that electrostatic repulsion among anionic headgroups is a key component in creating these structures.
Surfactants in Solution, 1991
Reviews in Computational Chemistry, 1998
Physical Review A, 1986
Well-resolved Ramsey fringes have been demonstrated using laser Stark spectroscopy of CH3F in a m... more Well-resolved Ramsey fringes have been demonstrated using laser Stark spectroscopy of CH3F in a molecular beam with two interaction regions. Fringe separations as low as 155 kHz were obtained. The interaction regions were produced by masks containing slits placed in the Gaussian-profile beam of a cw CO2 laser. Population inversion resulting from a frequency sweep associated with the curvature of
Molecular Physics, 1996
In computer simulations of water between hydrophobic walls the results exhibit a strong dependenc... more In computer simulations of water between hydrophobic walls the results exhibit a strong dependence upon the boundary conditions applied. With the minimum image (MI) convention the water molecules tend to be orientationally ordered throughout the simulation cell (Valleau, J. P., and Gardner, A. A., 1987, J. chem. Phys., 86, 4162) whereas, if a spherical cut-off (SC) is applied, strong orientational order is found only in the immediate vicinity of the surface (Lee, C. Y., McCammon, J. A., and Rossky, P. J., 1984, J. chem. Phys., 80, 4448). These conflicting observations have remained unresolved, and clearly raise troubling questions concerning the validity of simulation results for water between surfaces of all types. In the present paper we explore this problem by carrying out a detailed analysis of the results obtained with various types of boundary condition. These include Ewald calculations carried out with a central simulation cell adapted to describe the slab geometry of interest. It is shown that the order observed in MI calculations is an artefact of that particular truncation. The reason for this is isolated and discussed. Similar problems are found if a cylindrical cut-off is employed. The Ewald and SC methods gave qualitatively similar results for systems similar to those considered in previous simulations. However, for some geometries problems can also arise with the SC method. We conclude that in general the slab-adapted Ewald method is the safest choice.
Langmuir, 2000
A classical molecular dynamics simulation of a monolayer of sodium laurate (dodecanoate) at the a... more A classical molecular dynamics simulation of a monolayer of sodium laurate (dodecanoate) at the airwater interface has been carried out. We found highly curved, dynamic structural features within the soap monolayer during the simulation. Introduction of salt in the water appears to suppress the formation of these structural patterns, indicating that electrostatic repulsion among anionic headgroups is a key component in creating these structures.
The Journal of Chemical Physics, 1995
The Journal of Chemical Physics, 1994
The Journal of Chemical Physics, 1999
ABSTRACT Grand canonical Monte Carlo calculations are used to investigate the demixing transition... more ABSTRACT Grand canonical Monte Carlo calculations are used to investigate the demixing transition in model ionic solutions where the solvent is explicitly included. Charged hard sphere ions in hard sphere, dipolar hard sphere and quadrupolar hard sphere solvents are considered and the results are compared with the primitive (continuum solvent) model. For all solvents considered, it is found that the demixing transition is in the same general region of the phase diagram and is roughly described by liquid-vapor equilibrium in the primitive model. However, details such as the precise location of the critical point and the width of the unstable region depend upon the exact nature of the solvent. © 1999 American Institute of Physics.
The Journal of Chemical Physics, 1997
The modeling and nature of the physisorption of water at the metal (Hg)-water interface is explor... more The modeling and nature of the physisorption of water at the metal (Hg)-water interface is explored in this paper. We have evaluated potential models that fit into three general classes that are employed in the literature. These classes are distinguished by the manner in which the isotropic interactions between the metal and the water are modeled: namely, as non-attractive, weakly
The Journal of Chemical Physics, 1995
Current Opinion in Colloid & Interface Science, 2000
Major advances have been made at several levels of computer simulation of surfactant solutions. A... more Major advances have been made at several levels of computer simulation of surfactant solutions. Atomistic level studies of preassembled surfactant structures have become fairly routine. The development of structure in surfactant solutions has now been studied using ...