Computational simulation of biomolecules can provide important insights into protein design, prot... more Computational simulation of biomolecules can provide important insights into protein design, protein-ligand binding calculations, and ab initio biomolecular folding, among other applications. Accurate treatment of the solvent environment is essential in such applications, but use of explicit solvent can add considerable cost. Implicit treatment of solvent effects using a dielectric continuum model is an attractive alternative to explicit solvation since it is able to describe solvation effects without the inclusion of solvent degrees of freedom. Previously, we described the development and parameterization of implicit solvent models for small molecules. Here, we extend the parameterization of the generalized Kirkwood (GK) implicit solvent model for use with biomolecules described by the AMOEBA force field via the addition of interstitial space corrections to account for biomolecular geometry. These corrections include updating pairwise descreening scale factors to be element-specifi...
A comparative study of the interactions of rat cellular retinol-binding protein (CRBP) and cellul... more A comparative study of the interactions of rat cellular retinol-binding protein (CRBP) and cellular retinol-binding protein I1 (CRBP 11) with a number of synthetic phenyl-substituted analogs of all-trans-reti-no1 was performed using fluorescence and nuclear magnetic resonance analysis. These studies indicate that CRBP I1 is more sensitive to modifications of the ring moiety than CRBP. Removal of the two methyl substituents on the ring which are ortho to the polyene chain abolishes binding to CRBP 11. Conformational analysis of the ligands indicates that these two methyl groups influence the planarity of the ligand. The identification of monospecific ligands may prove useful for studying the physiological roles of these two proteins. Cellular retinol-binding protein (CRBP)' and cellular retinol-binding protein I1 (CRBP 11) are homologous cytoplasmic proteins that bind all-trans-retinol and all-trans-retinaldehyde. Although these two proteins share 56% amino acid sequence identity , they exhibit very different tissue distributions. CRBP I1 is confined to the columnar absorptive cells (enterocytes) on small intestinal villi in adult animals, where it represents -1% of the cytosolic proteins and is 1000-fold more abundant than CRBP Crow and Ong, 1985). In contrast CRBP is present in a wide variety of tissues, including liver, kidney, and testis . These differences in CRBP and CRBP I1 gene expression strongly suggest that these two proteins serve different physiological functions and that CRBP I1 is specifically adapted for intestinal absorption and metabolism of retinol. MacDonald and Ong (1987) reported that retinol is a better substrate for esterification by intestinal microsomes in vitro when it is presented bound to CRBP I1 rather than to CRBP. have reported in vitro studies suggesting that CRBP is involved in mediating the conversion of retinol
Computational protein design, ab initio protein/RNA folding, and protein-ligand screening can be ... more Computational protein design, ab initio protein/RNA folding, and protein-ligand screening can be too computationally demanding for explicit treatment of solvent. For these applications, implicit solvent offers a compelling alternative, which we describe here for the polarizable atomic multipole AMOEBA force field based on three treatments of continuum electrostatics: numerical solutions to the Poisson-Boltzmann equation (PBE), the domain-decomposition Conductor-like Screening Model (ddCOSMO) approximation to the PBE, and the analytic generalized Kirkwood (GK) approximation. The continuum electrostatic models are combined with a nonpolar estimator based on novel cavitation and dispersion terms. Electrostatic model parameters are numerically optimized using a least squares style target function based on a library of 103 small molecule solvation free energy differences. Mean signed errors for the APBS, ddCOSMO, and GK models are 0.05, 0.00, and 0.00 kcal/mol, respectively, while the me...
von Willebrand disease (vWD) is a common, autosomally inherited, bleeding disorder caused by quan... more von Willebrand disease (vWD) is a common, autosomally inherited, bleeding disorder caused by quantitative and/or qualitative deficiency of von Willebrand factor (vWF). We describe two families with a variant form of vWD where affected members of both families have borderline or low vWF antigen levels, normal vWF multimer patterns, disproportionately low ristocetin cofactor activity, and significant bleeding symptoms. Whereas ristocetin-induced binding of plasma vWF from affected members of both families to fixed platelets was reduced, botrocetin-induced platelet binding was normal. The sequencing of genomic DNA identified unique missense mutations in each family in the vWF exon 28. In Family A, a missense mutation at nucleotide 4105T → A resulted in a Phe606Ile amino acid substitution (F606I) and in Family B, a missense mutation at nucleotide 4273A → T resulted in an Ile662Phe amino acid substitution (I662F). Both mutations are within the large disulfide loop between Cys509 and Cys6...
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific r... more HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
We present a novel quantum mechanical/molecular mechanics (QM/MM) approach in which a quantum sub... more We present a novel quantum mechanical/molecular mechanics (QM/MM) approach in which a quantum subsystem is coupled to a classical subsystem described by the AMOEBA polarizable force field. Our approach permits mutual polarization between the QM and MM subsystems, effected through multipolar electrostatics. Self-consistency is achieved for both the QM and MM subsystems through a total energy minimization scheme. We provide an expression for the Hamiltonian of the coupled QM/MM system, which we minimize using gradient methods. The QM subsystem is described by the onetep linear-scaling DFT approach, which makes use of strictly localized orbitals expressed in a set of periodic sinc basis functions equivalent to plane waves. The MM subsystem is described by the multipolar, polarizable force field AMOEBA, as implemented in tinker. Distributed multipole analysis is used to obtain, on the fly, a classical representation of the QM subsystem in terms of atom-centered multipoles. This auxiliar...
We report the iAMOEBA ("inexpensive AMOEBA") classical polarizable water model. The iAMOEBA model... more We report the iAMOEBA ("inexpensive AMOEBA") classical polarizable water model. The iAMOEBA model uses a direct approximation to describe electronic polarizability, in which the induced dipoles are determined directly from the permanent multipole electric fields and do not interact with one another. The direct approximation reduces the computational cost relative to a fully polarizable model such as AMOEBA. The model is parameterized using ForceBalance, a systematic optimization method that simultaneously utilizes training data from experimental measurements and high-level ab initio calculations. We show that iAMOEBA is a highly accurate model for water in the solid, liquid, and gas phases, with the ability to fully capture the effects of electronic polarization and predict a comprehensive set of water properties beyond the training data set including the phase diagram. The increased accuracy of iAMOEBA over the fully polarizable AMOEBA model demonstrates ForceBalance as a method that allows the researcher to systematically improve empirical models by efficiently utilizing the available data.
Potential smoothing, a deterministic analog of stochastic simulated annealing, is a powerful para... more Potential smoothing, a deterministic analog of stochastic simulated annealing, is a powerful paradigm for the solution of conformational search problems that require extensive sampling, and should be a useful tool in computational approaches to structure prediction and refinement. A novel potential smoothing and search (PSS) algorithm has been developed and applied to predict the packing of transmembrane helices. The highlight of this method is the efficient manner in which it circumvents the combinatorial explosion associated with the large number of minima on multidimensional potential energy surfaces in order to converge to the global energy minimum. Here we show how our potential smoothing and search method succeeds in finding the global minimum energy structure for the glycophorin A (GpA) transmembrane helix dimer by optimizing interhelical van der Waals interactions over rigid and semi-rigid helices. Structures obtained from our ab initio predictions are in close agreement wit...
Proteins: Structure, Function, and Bioinformatics, 2014
Helices are important structural/recognition elements in proteins and peptides. Stability and con... more Helices are important structural/recognition elements in proteins and peptides. Stability and conformational differences between helices composed of αand β-amino acids as scaffolds for mimicry of helix recognition has become a theme in medicinal chemistry. Furthermore, helices formed by β-amino acids are experimentally more stable than those formed by α-amino acids. This is paradoxical because the larger sizes of the hydrogen-bonding rings required by the extra methylene groups should lead to entropic destabilization. In this study, molecular dynamics simulations using the second-generation force field, AMOEBA [1], explored the stability and hydrogen-bonding patterns of capped oligo-β-alanine, oligoalanine and oligoglycine dodecamers in water. The MD simulations showed that oligo-β-alanine has strong acceptor+2 hydrogen bonds, but surprisingly did not contain a large content of 3 12 -helical structures, possibly due to the sparse distribution of the 3 12 -helical structure and other structures with acceptor+2 hydrogen bonds. On the other hand, despite its backbone flexibility, the β-alanine dodecamer had more stable and persistent <3.0 Å hydrogen bonds. Its structure was dominated more by multicentered hydrogen bonds than either oligoglycine and oligoalanine helices. The 31 (PII) helical structure, prevalent in oligoglycine and oligoalanine, does not appear to be stable in oligo-β-alanine indicating its competition with other structures (stacking structure as indicated by MD analyses). These differences are among the factors that shape helical structural preferences and the relative stabilities of these three oligopeptides.
We report the iAMOEBA (i.e. "inexpensive AMOEBA") classical polarizable water model. iAMOEBA uses... more We report the iAMOEBA (i.e. "inexpensive AMOEBA") classical polarizable water model. iAMOEBA uses a direct approximation to describe electronic polarizability, which reduces the computational cost relative to a fully polarizable model such as AMOEBA. The model is parameterized using ForceBalance, a systematic optimization method that simultaneously utilizes training data from experimental measurements and high-level ab initio calculations. We show that iAMOEBA is a highly accurate model for water in the solid, liquid, and gas phases, with the ability to fully capture the effects of electronic polarization and predict a comprehensive set of water properties beyond the training data set including the phase diagram. The increased accuracy of iAMOEBA over the fully polarizable AMOEBA model demonstrates ForceBalance as a method that allows the researcher to systematically improve empirical models by optimally utilizing the available data.
Molecular force fields have been approaching a generational transition over the past several year... more Molecular force fields have been approaching a generational transition over the past several years, moving away from well-established and well-tuned, but intrinsically limited, fixed point charge models towards more intricate and expensive polarizable models that should allow more accurate description of molecular properties. The recently introduced AMOEBA force field is a leading
The temperature and pressure dependence of the previously developed polarizable atomic-multipole-... more The temperature and pressure dependence of the previously developed polarizable atomic-multipole-based AMOEBA water potential is explored. The energetic, structural, and dynamical properties of liquid water are investigated via molecular dynamics simulations at various temperatures ranging from 248 K to 360 K and pressures up to 5000 atm. The AMOEBA model, derived solely from known gas-phase and room-temperature liquid properties, produces a maximum liquid density around 290 K at 1 atm. The quantitative agreement between AMOEBA and experiment is good in general for density, heat of vaporization, radial distribution functions, magnetic shielding, self-diffusion, and static dielectric constant. Based on comparison of two variants of AMOEBA water, as well as results from other water potentials, it is suggested that the temperature at which the maximum density occurs is closely related to the tetrahedral hydrogen-bonding network in the bulk. Explicit dipole polarization and internal geometry in the liquid play vital roles in determining the selfdiffusion and dielectric constants. The development of the AMOEBA model demonstrates that a realistic and well-balanced atomic potential requires a sophisticated electrostatic description and inclusion of many-body polarization. Within the current polarizable atomic multipole framework, a potential derived from limited gas phase and condensed phase properties can be applied across a range of physical and thermodynamic environments.
Global energy optimization of a molecular system is difficult due to the well-known "multiple min... more Global energy optimization of a molecular system is difficult due to the well-known "multiple minimum" problem. The rugged potential energy surface (PES) characteristic of multidimensional systems can be transformed reversibly using potential smoothing to generate a new surface that is easier to search for favorable configurations. The diffusion equation method (DEM) is one example of a potential smoothing algorithm. Potential smoothing as implemented in DEM is intuitively appealing and has certain appropriate statistical mechanical properties, but often fails to identify the global minimum even for relatively small problems. In the present paper, extensions to DEM capable of correcting its empirical behavior are systematically investigated. Two types of local search (LS) procedures are applied during the reversing schedule from the smooth deformed PES to the undeformed surface. Changes needed to generate smoothable versions of standard molecular mechanics force fields such as AMBER/OPLS and MM2 are also described. The resulting methods are applied in an attempt to determine the global energy minimum for a variety of systems in different coordinate representations. The problems studied include argon clusters, cycloheptadecane, capped polyalanine, and the docking of R-helices. Depending on the specific problem, potential smoothing and search (PSS) is performed in Cartesian, torsional, or rigid body space. For example, PSS finds a very low energy structure for cycloheptadecane with much greater efficiency than a search restricted to the undeformed potential surface. It is shown that potential smoothing is characterized by three salient features. As the level of smoothing is increased, unique minima merge into a common basin, crossings can occur in the relative energies of a pair of minima, and the spatial locations of minima are shifted due to the averaging effects of smoothing. Local search procedures improve the ability of smoothing methods to locate global minima because they facilitate the post facto correction of errors due to energy crossings that may have occurred at higher levels of smoothing. PSS methods should serve as useful tools for global energy optimization on a variety of difficult problems of practical interest.
The stereochemistry of the marine eicosanoid, hybrldalactone, has been determined experimentally ... more The stereochemistry of the marine eicosanoid, hybrldalactone, has been determined experimentally to be as in 2, in accord with a proposed scheme of biosynthesis from eicosapentaenoic acid. Recently a novel eicosanoid, designated hybridalactone, was isolated from the marine alga Laurencia hybrida and was assigned gross structureL on the basis of proton magnetic resonance (pmr) studies. 1 A partial assignment of stereochemistry was also made which included: (1) relative arrangement of substituents on the B-membered ring, (2) cts relationship between carbons on the S-membered ring, and (3) Z-arrangement of the 5,6-and 8,9-double bonds. 1 In this note we present evidence for the complete stereochemistry of hybridalactone (2 ) and also describe a possible pathway to biosynthesis, which correctly predicted absolute stereochemistry. Research on the total synthesis of hybridalactone, to be published separately, has completely confirmed the assignment of stereoformula 2t.o hybridalactone. The studies on stereochemistry and synthesis were initiated before a sample of natural hybridalactone was avatlable to us and consisted of a combined analysis of molecular mechanics calculations, published' pmr data and biogenesis. The vlcinal stereorelationship at C-14/15 was clarlfled first from pmr data and computer calculations performed on a simplified structure, a A 11,12 -olefin with an L-prcpyl group instead of ethylcyclopropyl at C-15. For clarity these results will be discussed relative to the finally determined 5 configuration at C-14. Random starting conformations were generated by a modified EMBED distance-geometry technique.
The ab initio folding problem can be divided into two sequential tasks of approximately equal com... more The ab initio folding problem can be divided into two sequential tasks of approximately equal computational complexity: the generation of native-like backbone folds and the positioning of side chains upon these backbones. The prediction of side-chain conformation in this context is challenging, because at best only the near-native global fold of the protein is known. To test the effect of displacements in the protein backbones on side-chain prediction for folds generated ab initio, sets of near-native backbones (I 4 A ˚C␣ RMS error) for four small proteins were generated by two methods. The steric environment surrounding each residue was probed by placing the side chains in the native conformation on each of these decoys, followed by torsion-space optimization to remove steric clashes on a rigid backbone. We observe that on average 40% of the 1 angles were displaced by 40°or more, effectively setting the limits in accuracy for sidechain modeling under these conditions. Three different algorithms were subsequently used for prediction of side-chain conformation. The average prediction accuracy for the three methods was remarkably similar: 49% to 51% of the 1 angles were predicted correctly overall (33% to 36% of the 1؉2 angles). Interestingly, when the inter-side-chain interactions were disregarded, the mean accuracy increased. A consensus approach is described, in which side-chain conformations are defined based on the most frequently predicted angles for a given method upon each set of near-native backbones. We find that consensus modeling, which de facto includes backbone flexibility, improves side-chain prediction: 1 accuracy improved to 51-54% (36-42% of 1؉2). Implications of a consensus method for ab initio protein structure prediction are discussed. Pro-
Proceedings of the National Academy of Sciences, 1998
A large superfamily of transmembrane receptors control cellular responses to diverse extracellula... more A large superfamily of transmembrane receptors control cellular responses to diverse extracellular signals by catalyzing activation of specific types of heterotrimeric GTP-binding proteins. How these receptors recognize and promote nucleotide exchange on G protein α subunits to initiate signal amplification is unknown. The three-dimensional structure of the transducin (Gt) α subunit C-terminal undecapeptide Gtα(340–350) IKENLKDCGLF was determined by transferred nuclear Overhauser effect spectroscopy while it was bound to photoexcited rhodopsin. Light activation of rhodopsin causes a dramatic shift from a disordered conformation of Gtα(340–350) to a binding motif with a helical turn followed by an open reverse turn centered at Gly-348, a helix-terminating C capping motif of an α L type. Docking of the NMR structure to the GDP-bound x-ray structure of Gt reveals that photoexcited rhodopsin promotes the formation of a continuous helix over residues 325–346 terminated by the C-terminal ...
Proceedings of the National Academy of Sciences, 1995
Inositol polyphosphate 1-phosphatase, inositol monophosphate phosphatase, and fructose 1,6-bispho... more Inositol polyphosphate 1-phosphatase, inositol monophosphate phosphatase, and fructose 1,6-bisphosphatase share a sequence motif, Asp-Pro-(Ile or Leu)-Asp-(Gly or Ser)-(Thr or Ser), that has been shown by crystallographic and mutagenesis studies to bind metal ions and participate in catalysis. We compared the six alpha-carbon coordinates of this motif from the crystal structures of these three phosphatases and found that they are superimposable with rms deviations ranging from 0.27 to 0.60 A. Remarkably, when these proteins were aligned by this motif a common core structure emerged, defined by five alpha-helices and 11 beta-strands comprising 155 residues having rms deviations ranging from 1.48 to 2.66 A. We used the superimposed structures to align the sequences within the common core, and a distant relationship was observed suggesting a common ancestor. The common core was used to align the sequences of several other proteins that share significant similarity to inositol monophosp...
Thermodynamic measurements of the solvation of salts and electrolytes are relatively straightforw... more Thermodynamic measurements of the solvation of salts and electrolytes are relatively straightforward, but it is not possible to separate total solvation free energies into distinct cation and anion contributions without reference to an additional extrathermodynamic assumption. The present work attempts to resolve this difficulty using molecular dynamics simulations with the AMOEBA polarizable force field and perturbation techniques to directly compute absolute solvation free energies for potassium, sodium, and chloride ions in liquid water and formamide. Corresponding calculations are also performed with two widely used nonpolarizable force fields. The simulations with the polarizable force field accurately reproduce in vacuo quantum mechanical results, experimental ion-cluster solvation enthalpies, and experimental solvation free energies for whole salts, while the other force fields do not. The results indicate that calculations with a polarizable force field can capture the thermodynamics of ion solvation and that the solvation free energies of the individual ions differ by several kilocalories from commonly cited values.
The conformations and stabilities of the β-hairpin model peptides of Waters 1,2 have been experim... more The conformations and stabilities of the β-hairpin model peptides of Waters 1,2 have been experimentally characterized as a function of lysine ε-methylation. These models were developed to explore molecular recognition of known epigenetic recognition motifs. This system offered an opportunity to computationally examine the role of cation-π interactions, desolvation of the εmethylated ammonium groups, and aromatic/aromatic interactions on the observed differences in NMR spectra. AMOEBA, a second-generation force field 4 , was chosen as it includes both multipole electrostatics and polarizability thought to be essential to accurately characterize such interactions. Independent parameterization of ε-methylated amines was required from which aqueous solvation free energies were estimated and shown to agree with literature values. Molecular dynamics simulations (100 ns) using the derived parameters with model peptides, such , where n = 0, 1, 2, or 3, were conducted in explicit solvent. Distances between the centers of the indole rings of the two-tryptophan residues, 2 and 4, and the ε-methylated ammonium group on Lys-9 as well as the distance between the Nand C-termini were monitored to estimate the strength and orientation of the cation-π and aromatic/aromatic interactions. In agreement with the experimental data, the stability of the βhairpin increased significantly with lysine ε-methylation. The ability of MD simulations to reproduce the observed NOEs for the four peptides was further estimated for the monopole-based force fields, AMBER, CHARMM, and OPLSAA. AMOEBA correctly predicted over 80% of the observed NOEs for all four peptides, while the three-monopole force fields were 40-50% predictive in only two cases and approximately 10% in the other ten examples. Preliminary analysis suggests that the decreased cost of desolvation of the substituted ammonium group significantly compensated for the reduced cation-π interaction resulting from the increased separation due to steric bulk of the ε-methylated amines.
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Papers by Jay Ponder