CiteULike: Author Berne

Role of the Active-Site Solvent in the Thermodynamics of Factor Xa Ligand Binding

R Abel — 2008-07-15T14:46:35-00:00

J. Am. Chem. Soc., Vol. 130, No. 9. (5 March 2008), pp. 2817-2831.

Abstract: Understanding the underlying physics of the binding of small-molecule ligands to protein active sites is a key objective of computational chemistry and biology. It is widely believed that displacement of water molecules from the active site by the ligand is a principal (if not the dominant) source of binding free energy. Although continuum theories of hydration are routinely used to describe the contributions of the solvent to the binding affinity of the complex, it is still an unsettled question as to whether or not these continuum solvation theories describe the underlying molecular physics with sufficient accuracy to reliably rank the binding affinities of a set of ligands for a given protein. Here we develop a novel, computationally efficient descriptor of the contribution of the solvent to the binding free energy of a small molecule and its associated receptor that captures the effects of the ligand displacing the solvent from the protein active site with atomic detail. This descriptor quantitatively predicts (R2 = 0.81) the binding free energy differences between congeneric ligand pairs for the test system factor Xa, elucidates physical properties of the active-site solvent that appear to be missing in most continuum theories of hydration, and identifies several features of the hydration of the factor Xa active site relevant to the structure-activity relationship of its inhibitors.

Direct Observation of Stretched-Exponential Relaxation in Low-Temperature Lennard-Jones Systems Using the Cage Correlation Function

Eran Rabani — 2008-03-24T22:16:42-00:00

Physical Review Letters, Vol. 82, No. 18. (3 May 1999), 3649.

We report on the direct observation of stretched exponential relaxation in low-temperature monatomic Lennard-Jones systems which were cooled slowly from the liquid phase to form crystals with a large number of defects. We use the cage correlation function [E. Rabani; J. D. Gezelter; and B. J. Berne; J. Chem. Phys. 107 ; 6867 (1997)] which measures changes in atomic surroundings to observe the stretched exponential relaxations. We obtain a distribution of hopping rates assuming that the origin of the Kohlrausch-Williams-Watts law is from static disorder in the distribution of barrier heights.

Calculating the hopping rate for diffusion in molecular liquids: CS[sub 2]

Daniel Gezelter — 2008-06-20T07:20:57-00:00

The Journal of Chemical Physics, Vol. 110, No. 7. (1999), pp. 3444-3452.

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Calculating the hopping rate for self-diffusion on rough potential energy surfaces: Cage correlations

Eran Rabani — 2007-11-25T18:58:07-00:00

The Journal of Chemical Physics, Vol. 107, No. 17. (1997), pp. 6867-6876.

Email Address:

Reversible multiple time scale molecular dynamics

M Tuckerman — 2008-03-28T12:02:22-00:00

J. Chem. Phys., Vol. 97 (August 1992), pp. 1990-2001.

Not Available

Can a continuum solvent model reproduce the free energy landscape of a beta -hairpin folding in water?

Ruhong Zhou — 2007-11-05T15:30:15-00:00

Proceedings of the National Academy of Sciences, Vol. 99, No. 20. (1 October 2002), pp. 12777-12782.

The folding free energy landscape of the C-terminal beta-hairpin of protein G is explored using the surface-generalized Born (SGB) implicit solvent model, and the results are compared with the landscape from an earlier study with explicit solvent model. The OPLSAA force field is used for the beta-hairpin in both implicit and explicit solvent simulations, and the conformational space sampling is carried out with a highly parallel replica-exchange method. Surprisingly, we find from exhaustive conformation space sampling that the free energy landscape from the implicit solvent model is quite different from that of the explicit solvent model. In the implicit solvent model some nonnative states are heavily overweighted, and more importantly, the lowest free energy state is no longer the native beta-strand structure. An overly strong salt-bridge effect between charged residues (E42, D46, D47, E56, and K50) is found to be responsible for this behavior in the implicit solvent model. Despite this, we find that the OPLSAA/SGB energies of all the nonnative structures are higher than that of the native structure; thus the OPLSAA/SGB energy is still a good scoring function for structure prediction for this beta-hairpin. Furthermore, the beta-hairpin population at 282 K is found to be less than 40% from the implicit solvent model, which is much smaller than the 72% from the explicit solvent model and approx80% from experiment. On the other hand, both implicit and explicit solvent simulations with the OPLSAA force field exhibit no meaningful helical content during the folding process, which is in contrast to some very recent studies using other force fields. 10.1073/pnas.142430099

Destruction of long-range interactions by a single mutation in lysozyme.

Ruhong Zhou — 2007-04-02T13:42:35-00:00

Proc Natl Acad Sci U S A (26 March 2007)

We propose a mechanism, based on a >/=10-micros molecular dynamics simulation, for the surprising misfolding of hen egg-white lysozyme caused by a single mutation (W62G). Our simulations of the wild-type and mutant lysozymes in 8 M urea solution at biological temperature (with both pH 2 and 7) reveal that the mutant structure is much less stable than that of the wild type, with the mutant showing larger fluctuations and less native-like contacts. Analysis of local contacts reveals that the Trp-62 residue is the key to a cooperative long-range interaction within the wild type, where it acts like a bridge between two neighboring basic residues. Thus, a native-like cluster or nucleation site can form near these residues in the wild type but not in the mutant. The time evolution of the secondary structure also exhibits a quicker loss of the beta-sheets in the mutant than in the wild type, whereas some of the alpha-helices persist during the entire simulation in both the wild type and the mutant in 8 M urea (even though the tertiary structures are basically all gone). These findings, while supporting the general conclusions of a recent experimental study by Dobson and coworkers [Klein-Seetharam J, Oikama M, Grimshaw SB, Wirmer J, Duchardt E, Ueda T, Imoto T, Smith LJ, Dobson CM, Schwalbe H (2002) Science 295:1719-1722], provide a detailed but different molecular picture of the misfolding mechanism.

Games People Play: The basic handbook of transactional analysis.

Eric Berne — 2007-04-30T09:39:14-00:00

(27 August 1996)

<i>We think we’re relating to other people–but actually we’re all playing games.<br></i><br>Forty years ago, <i>Games People Play </i>revolutionized our understanding of what <i>really</i> goes on during our most basic social interactions. More than five million copies later, Dr. Eric Berne’s classic is as astonishing–and revealing–as it was on the day it was first published. This anniversary edition features a new introduction by Dr. James R. Allen, president of the International Transactional Analysis Association, and Kurt Vonnegut’s brilliant <i>Life</i> magazine review from 1965.<br>We play games all the time–sexual games, marital games, power games with our bosses, and competitive games with our friends. Detailing status contests like “Martini” (I know a better way), to lethal couples combat like “If It Weren’t For You” and “Uproar,” to flirtation favorites like “The Stocking Game” and “Let’s You and Him Fight,” Dr. Berne exposes the secret ploys and unconscious maneuvers that rule our intimate lives.<br>Explosive when it first appeared, <i>Games People Play </i>is now widely recognized as the most original and influential popular psychology book of our time. It’s as powerful and eye-opening as ever.

USF1 gene variants contribute to metabolic traits in men in a longitudinal 32-year follow-up study.

K Auro — 2008-01-03T07:42:41-00:00

Diabetologia (21 December 2007)

AIMS/HYPOTHESIS: Genetic variants of upstream transcription factor 1 (USF1) have previously been associated with dyslipidaemias in family studies. Our aim was to further address the role of USF1 in metabolic syndrome and cardiovascular traits at the population level in a large Swedish male cohort (n = 2,322) with multiple measurements for risk factors during 32 years of follow-up. METHODS: Participants, born in 1920-1924, were examined at 50, 60, 70 and 77 years of age. The follow-up period for cardiovascular events was 1970-2002. We genotyped three haplotype tagging polymorphisms capturing the major allelic variants of USF1. RESULTS: SNP rs2774279 was associated with the metabolic syndrome. The minor allele of rs2774279 was less common among individuals with metabolic syndrome than among healthy controls [p = 0.0029 when metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III; p = 0.0073 when defined according to the International Diabetes Federation (IDF)]. The minor allele of rs2774279 was also associated with lower BMI, lower fasting glucose values and higher HDL-cholesterol concentrations in longitudinal analyses. With SNP rs2073658, a borderline association with metabolic syndrome was observed (p = 0.036, IDF), the minor allele being the risk-increasing allele. The minor allele of rs2073658 also associated with higher total and LDL-cholesterol, apolipoprotein B-100 and lipoprotein(a) concentrations in longitudinal analyses. Importantly, these trends with respect to the allelic variants prevailed throughout the follow-up time of three decades. CONCLUSIONS/INTERPRETATION: Our results suggest that USF1 variants associate with the metabolic syndrome at population level and influence the cardiovascular risk factors throughout adulthood in a consistent, longitudinal manner.

Teacher Learning and the Acquisition of Professional Knowledge: An Examination of Research on Contemporary Professional Development

Suzanne Wilson — 2007-12-17T07:01:34-00:00

Reversible multiple time scale molecular dynamics

M Tuckerman — 2007-11-30T20:31:07-00:00

The Journal of Chemical Physics, Vol. 97, No. 3. (1992), pp. 1990-2001.

Erratum: ”Large scale simulation of macromolecules in solution: Combining the periodic fast multipole method with multiple time step integrators” [J. Chem. Phys. 106, 9835 (1997)]

F Figueirido — 2007-11-29T00:42:18-00:00

J. Chem. Phys., Vol. 107 (November 1997), 7002.

Not Available

Molecular Reorientation in Liquids and Gases

BJ Berne — 2007-11-27T17:34:51-00:00

The Journal of Chemical Physics, Vol. 49, No. 7. (1968), pp. 3125-3129.

Email Address:

Dynamic Light Scattering: With Applications to Chemistry, Biology, and Physics

Bruce Berne — 2007-11-24T19:53:59-00:00

(14 August 2000)

<div><div>This comprehensive introduction to principles underlying laser light scattering focuses on time dependence of fluctuations in fluid systems. It also serves as introduction to theory of time correlation functions, with chapters on projection operator techniques in statistical mechanics. Over 60 text figures. 1976 edition.<br></div></div>

The free energy landscape for beta hairpin folding in explicit water.

R Zhou — 2007-10-02T14:34:06-00:00

Proc Natl Acad Sci U S A, Vol. 98, No. 26. (18 December 2001), pp. 14931-14936.

The folding free energy landscape of the C-terminal beta hairpin of protein G has been explored in this study with explicit solvent under periodic boundary condition and OPLSAA force field. A highly parallel replica exchange method that combines molecular dynamics trajectories with a temperature exchange Monte Carlo process is used for sampling with the help of a new efficient algorithm P3ME/RESPA. The simulation results show that the hydrophobic core and the beta strand hydrogen bond form at roughly the same time. The free energy landscape with respect to various reaction coordinates is found to be rugged at low temperatures and becomes a smooth funnel-like landscape at about 360 K. In contrast to some very recent studies, no significant helical content has been found in our simulation at all temperatures studied. The beta hairpin population and hydrogen-bond probability are in reasonable agreement with the experiment at biological temperature, but both decay more slowly than the experiment with temperature.

Motifs for molecular recognition exploiting hydrophobic enclosure in protein-ligand binding

Tom Young — 2007-01-17T18:27:06-00:00

PNAS, Vol. 104, No. 3. (16 January 2007), pp. 808-813.

The thermodynamic properties and phase behavior of water in confined regions can vary significantly from that observed in the bulk. This is particularly true for systems in which the confinement is on the molecular-length scale. In this study, we use molecular dynamics simulations and a powerful solvent analysis technique based on inhomogenous solvation theory to investigate the properties of water molecules that solvate the confined regions of protein active sites. Our simulations and analysis indicate that the solvation of protein active sites that are characterized by hydrophobic enclosure and correlated hydrogen bonds induce atypical entropic and enthalpic penalties of hydration. These penalties apparently stabilize the protein-ligand complex with respect to the independently solvated ligand and protein, which leads to enhanced binding affinities. Our analysis elucidates several challenging cases, including the super affinity of the streptavidin-biotin system. 10.1073/pnas.0610202104

Changes in skin barrier function following long-term treatment with moisturizers, a randomized controlled trial

Buraczewska — 2007-02-12T06:49:05-00:00

British Journal of Dermatology, Vol. 156, No. 3. (March 2007), pp. 492-498.

Effect of Ions on the Hydrophobic Interaction between Two Plates

R Zangi — 2007-05-10T00:55:56-00:00

J. Am. Chem. Soc., Vol. 129, No. 15. (18 April 2007), pp. 4678-4686.

Abstract: We use molecular dynamics simulations to investigate the solvent mediated attraction and drying between two nanoscale hydrophobic surfaces in aqueous salt solutions. We study these effects as a function of the ionic charge density, that is, the ionic charge per unit ionic volume, while keeping the ionic diameter fixed. The attraction is expressed by a negative change in the free energy as the plates are brought together, with enthalpy and entropy changes that both promote aggregation. We find a strong correlation between the strength of the hydrophobic interaction and the degree of preferential binding/exclusion of the ions relative to the surfaces. The results show that amplification of the hydrophobic interaction, a phenomenon analogous to salting-out, is a purely entropic effect and is induced by high-charge-density ions that exhibit preferential exclusion. In contrast, a reduction of the hydrophobic interaction, analogous to salting-in, is induced by low-charge-density ions that exhibit preferential binding, the effect being either entropic or enthalpic. Our findings are relevant to phenomena long studied in solution chemistry, as we demonstrate the significant, yet subtle, effects of electrolytes on hydrophobic aggregation and collapse.

Signatures of hydrophobic collapse in extended proteins captured with force spectroscopy.

Kirstin A Walther — 2007-05-09T01:33:26-00:00

Proc Natl Acad Sci U S A (30 April 2007)

We unfold and extend single proteins at a high force and then linearly relax the force to probe their collapse mechanisms. We observe a large variability in the extent of their recoil. Although chain entropy makes a small contribution, we show that the observed variability results from hydrophobic interactions with randomly varying magnitude from protein to protein. This collapse mechanism is common to highly extended proteins, including nonfolding elastomeric proteins like PEVK from titin. Our observations explain the puzzling differences between the folding behavior of highly extended proteins, from those folding after chemical or thermal denaturation. Probing the collapse of highly extended proteins with force spectroscopy allows separation of the different driving forces in protein folding.

Vegetation dynamics in southern France during the last 30 ky BP in the light of marine palynology

Celia Beaudouin — 2007-02-14T09:28:33-00:00

Quaternary Science Reviews, Vol. In Press, Corrected Proof

The composition of the glacial vegetation of southern French plains has been a matter of debate for several decades. Vegetation is considered as steppic according to French and Spanish lacustrine pollen records whereas cave deposits suggest the presence of mesothermophilous trees through the Last Glacial Maximum. In our paper, we display new palynological records from marine sediments of the Gulf of Lions. They indicate the presence of Abies, Picea and deciduous Quercus in the Gulf of Lions, certainly located in the drainage basins of the Pyreneo-Languedocian rivers. These populations that were sensitive to short climatic events during Marine Isotopic Stage 2 could have been linked to northeastern Spanish and southeastern French relicts already evidenced by phylogenetic data. These trees were absent from the Rhone drainage basin during the deglaciation and certainly also disappeared from the Pyreneo-Languedocian drainage basins from ca 17 to 15 ky cal BP. Finally, the Last Glacial Maximum does not appear as stable, cold and dry as previously thought.

Combined fluctuating charge and polarizable dipole models: Application to a five-site water potential function

Harry Stern — 2006-04-24T15:30:06-00:00

The Journal of Chemical Physics, Vol. 115, No. 5. (2001), pp. 2237-2251.

We present a general formalism for polarizable electrostatics based on fluctuating bond-charge increments and polarizable dipoles and its application to a five-site model for water. The parametrization is based largely on quantum-chemical calculations and should be easily transferable to other molecules. To examine basis-set effects we parametrized two models from two sets of quantum calculations, using the aug-cc-pVTZ and aug-cc-pVQZ basis sets. We computed several gas-phase and condensed-phase properties and compared with experiment or ab initio calculations as available. The models are quite similar and give condensed-phase properties at ambient conditions that are in reasonable accord with experiment, but evince errors consistent with a liquid-state dipole moment that is slightly too large. The model fit to the aug-cc-pVTZ basis set has a smaller liquid-phase dipole moment and thus gives a somewhat better description of liquid water at ambient conditions. This model also performs well away from room temperature, deviating less than 2% from the experimental density from 0 to 100 °C, and showing good agreement with experimental radial distribution functions, although the temperature of maximum density (~20 °C) is slightly too high and the model somewhat underpredicts the persistence of the hydrogen-bond network at elevated temperatures. ©2001 American Institute of Physics.

Parametrizing a polarizable force field from ab initio data. I. The fluctuating point charge model

Jay Banks — 2006-04-24T15:27:01-00:00

The Journal of Chemical Physics, Vol. 110, No. 2. (1999), pp. 741-754.

We have developed a polarizable force field for peptides, using all-atom OPLS (OPLS-AA) nonelectrostatic terms and electrostatics based on a fluctuating charge model and fit to ab initio calculations of polarization responses. We discuss the fitting procedure, and specific techniques we have developed that are necessary in order to obtain an accurate, stable model. Our model is comparable to the best existing molecular mechanics force fields in reproducing quantum-chemical peptide energetics. It also accurately reproduces many-body effects in many cases. We believe that straightforward extensions of our linear-response electrostatic model will significantly improve the accuracy for those cases that the present model does not adequately address. ©1999 American Institute of Physics.

Constructing ab initio force fields for molecular dynamics simulations

Yi Liu — 2006-04-24T15:22:47-00:00

The Journal of Chemical Physics, Vol. 108, No. 12. (1998), pp. 4739-4755.

We explore and discuss several important issues concerning the derivation of many-body force fields from ab initio quantum chemical data. In particular, we seek a general methodology for constructing ab initio force fields that are "chemically accurate" and are computationally efficient for large-scale molecular dynamics simulations. We investigate two approaches for modeling many-body interactions in extended molecular systems. The interactions are adjusted to reproduce the many-body energy in small molecular clusters. Subsequently, the potential parameters affecting only pair interactions are then varied to reproduce the ab initio binding energy of dimers. This simple procedure is demonstrated in the design of a new polarizable force field of water. In particular, this new model incorporates the usual many-body interactions due to electrostatic polarization and a type of nonelectrostatic many-body interactions exhibited in bifurcated hydrogen-bonded systems. The static and dynamical properties predicted by the new ab initio water potential are in good agreement with the successful empirical fluctuating-charge potential of Rick et al. and with experiment. The aforementioned "cluster" approach is compared with an alternative method, which regards many-body interactions as manifestations of the electrostatic polarization properties of individual molecules. The effort required to build ab initio databases for force field parametrization is substantially reduced in this alternative method since only the monomer properties are of interest. We found intriguing differences between these two approaches. Finally our results point to the importance of discriminating ab initio data for force field parametrization. This is essentially a consequence of the simple functional forms employed to model molecular interactions, and is inevitable for large-scale molecular dynamics simulations. ©1998 American Institute of Physics.

Dynamical fluctuating charge force fields: Application to liquid water

Steven Rick — 2006-04-19T11:31:31-00:00

The Journal of Chemical Physics, Vol. 101, No. 7. (1994), pp. 6141-6156.

A new molecular dynamics model in which the point charges on atomic sites are allowed to fluctuate in response to the environment is developed and applied to water. The idea for treating charges as variables is based on the concept of electronegativity equalization according to which: (a) the electronegativity of an atomic site is dependent on the atom's type and charge and is perturbed by the electrostatic potential it experiences from its neighbors and (b) charge is transferred between atomic sites in such a way that electronegativities are equalized. The charges are treated as dynamical variables using an extended Lagrangian method in which the charges are given a fictitious mass, velocities, and kinetic energy and then propagated according to Newtonian mechanics along with the atomic degrees of freedom. Models for water with fluctuating charges are developed using the geometries of two common fixed-charge water potentials: the simple point charge (SPC) and the four-point transferable intermolecular potential (TIP4P). Both fluctuating charge models give accurate predictions for gas-phase and liquid state properties, including radial distribution functions, the dielectric constant, and the diffusion constant. The method does not introduce any new intermolecular interactions beyond those already present in the fixed charge models and increases the computer time by only a factor of 1.1, making this method tractable for large systems. The Journal of Chemical Physics is copyrighted by The American Institute of Physics.

Fluctuating Charge, Polarizable Dipole, and Combined Models: Parameterization from ab Initio Quantum Chemistry

HA Stern — 2006-04-19T07:48:36-00:00

J. Phys. Chem. B, Vol. 103, No. 22. (3 June 1999), pp. 4730-4737.

Development of an Accurate and Robust Polarizable Molecular Mechanics Force Field from ab Initio Quantum Chemistry

GA Kaminski — 2006-04-19T07:46:48-00:00

J. Phys. Chem. A, Vol. 108, No. 4. (29 January 2004), pp. 621-627.

Current Status of Clinical Islet Transplantation.

Olle Korsgren — 2005-05-26T09:05:16-00:00

Transplantation, Vol. 79, No. 10. (27 May 2005), pp. 1289-1293.

Islet transplantation is currently being explored as a treatment for patients with type 1 diabetes. At present, the number of patients becoming insulin-independent is rapidly increasing world-wide applying the transplantation protocol originally described by the group in Edmonton. A hallmark in this procedure is repeated infusions of islets obtained from 2 to 4 donors until normoglycemia is achieved. In order to establish islet transplantation as a widely accepted treatment modality, and make tolerance induction regimes applicable, it is essential that the donor:recipient ratio is brought down to 1:1. A conceivable strategy to achieve this goal in clinical islet transplantation is discussed.