An all atom force field for simulations of proteins and nucleic acids

Weiner, Scott J.; Kollman, Peter A.; Nguyen, Dzung T.; Case, David A.

doi:10.1002/jcc.540070216

Cited by 3,470 publications

(2,213 citation statements)

References 48 publications

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“…For bond lengths and angles these quadratic force-constants represent A i and B i in Eqn (1) and could be used directly. For dihedral angles, the periodicity of the potential was determined from the values of dihedral angels found in the structures and the C ij constants in Eqn (1) 40 .…”

Section: Parametrization Of the Zinc Ionmentioning

confidence: 99%

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Molecular dynamics simulations of alcohol dehydrogenase with a four‐ or five‐coordinate catalytic zinc ion

1995

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A detailed parameterization is presented of a zinc ion with one histidine and two cysteinate ligands, together with one or two water, hydroxide, aldehyde, alcohol, or alkoxide ligands. The parameterization is tailored for the active site of alcohol dehydrogenase and is obtained entirely from quantum chemical computations. The force‐field reproduces excellently the geometry of quantum chemically optimized zinc complexes as well as the crystallographic geometry of the active site of alcohol dehydrogenase and small organic structures. The parameterization is used in molecular dynamics simulations and molecular mechanical energy minimizations of alcohol dehydrogenase with a four‐ or five‐coordinate catalytic zinc ion. The active‐site zinc ion seems to prefer four‐coordination over five‐coordination by at least 36 kJ/mol. The only stable binding site of a fifth ligand at the active‐site zinc ion is opposite to the normal substrate site, in a narrow cavity behind the zinc ion. Only molecules of the size of water or smaller may occupy this site. There are large fluctuations in the geometry of the zinc coordination sphere. A four‐coordinate water molecule alternates frequently (every 7 ps) between the substrate site and the fifth binding site and even two five coordinate water molecules may interchange ligation sites without prior dissociation. Ligand exchange at the zinc ion probably proceeds by a dissociative mechanism. The results show that it is essential to allow for bond stretching degrees of freedom in molecular dynamics simulations to get a correct description of the dynamics of the metal coordination sphere; bond length constraints may restrict the accessible part of the phase space and therefore lead to qualitatively erroneous results. © 1995 Wiley‐Liss, Inc.

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Section: Parametrization Of the Zinc Ionmentioning

confidence: 99%

“…The force-field parameters of P and OS were taken from the AMBER 40 and XPLOR 41 force fields. The parameters of the negatively charged atom types were obtained from quantum chemical computations on HX -, CH 3 X -and CH 3 CH 2 X -, X=S or O, using the 6-31+G** basis sets.…”

Section: Parametrization Of the Zinc Ionmentioning

confidence: 99%

Molecular dynamics simulations of alcohol dehydrogenase with a four‐ or five‐coordinate catalytic zinc ion

1995

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“…The calculations were performed on Silicon Graphics workstations. Several molecular dynamics (MD) trajectories were calculated with the DISCOVER software using different parametrizations: CVFF (Consistent Valence Force Field) (11,12) and the AMBER program (Assisted Model Building with Energy Refinement) (13,14). In addition, other programs with different force fields, e.g.…”

Section: Preparation Of the Ligand A Mixture Of 1-o-[3ј-(trifluoroacmentioning

confidence: 99%

NMR-Based, Molecular Dynamics- and Random Walk Molecular Mechanics-Supported Study of Conformational Aspects of a Carbohydrate Ligand (Galβ1-2Galβ1-R) for an Animal Galectin in the Free and in the Bound State

Siebert

Gilleron

Kaltner

et al. 1996

Biochemical and Biophysical Research Communications

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The binding of a carbohydrate to a lectin may affect the conformation of the ligand. To address this question for the galectin from chicken liver, the conformation of Gal␤1-2Gal␤1-R was analyzed in the free and in the galectin-bound state with 2D-ROESY-and 1D-as well as 2D-transferred NOE-experiments. A computerassisted analysis of spatial parameters of the ligand by molecular dynamics (MD) and random walk molecular mechanics (RAMM) calculations, taking different dielectric constants from ⑀ ‫ס‬ 1 to ⑀ ‫ס‬ 80 and various force fields into account, were instrumental to define the energetic minima of the free state. NMR-derived interresidual distance constraints enabled a conformational mapping. The two overlapping interresidual distance constraints obtained from transferred-NOE experiments of the galectin-ligand complex clearly support the notion that the conformation of the disaccharide in the bound state is at least very close to its global energy minimum state in solution. © 1996 Academic Press, Inc.Protein-carbohydrate interactions can guide crucial physiological reactions such as cell adhesion, inter-and intracellular glycoprotein routing and regulation of various cellular functions (1, 2). Their evident importance prompts to analyze in detail the molecular characteristics of this type of recognition in solution. The combination of computer-assisted calculations of the conformation and NMR-based experiments for the free ligand and lectin-saccharide complex provides a suitable tool to address this question. It enables us to compare spatial parameters of a certain ligand before and after association with members of a lectin family with similar binding specificity, e.g. to galactosides. Agglutinins of this class mediate cell-matrix interactions and enhance immune functions (3-5). Due to the remarkable affinity of Gal␤1-2Gal␤1-R to the immunomodulatory Viscum album agglutinin, reported previously (6, 7), we have chosen to map conformational aspects of this high-affinity ligand for galactoside-binding lectins of organisms from different branches of the evolutionary tree. Herein, we report the first study in this area for an animal galectin. Transferred nuclear Overhauser effect (TRNOE)-based experiments in combination with conformational distance mapping, random walk molecular mechanics (RAMM) and molecular dynamics (MD) calculations indicate that the actual conformations of this disaccharide in the complex and in the free form are at least very similar.

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“…The positions of the hydrogen atoms in the lipase were calculated by the BIOPOLYMER module of SYBYL. Amino acid residues within a 6-A distance from any atom of the transition-state model were treated by the all-atom AMBER force field (Weiner et al, 1986), whereas the united atom AMBER force field (Weiner et al, 1984) was applied to the rest of the amino acid residues in the lipase. Water molecules were represented with use of the TIP3P water model (Jorgensen et al, 1983).…”

Section: Preparation Of Starting Models Of Lipase-transition State Comentioning

confidence: 99%

A structural basis for enantioselective inhibition of Candida rugosa lipase by long‐chain aliphatic alcohols

et al. 1996

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Molecular modeling showed that the enantiomers of heptyl2-methyldecanoate are productively bound to the active site of Candida rugosa lipase in quite different conformations. The fast-reacting S-enantiomer may well occupy the previously identified acyl-binding tunnel in the active site of the lipase. By contrast, the slow-reacting R-enantiomer must be bound to the active site, leaving the tunnel empty to allow the formation of two catalytically essential hydrogen bonds between His 449 of the catalytic triad and the transition state of the catalyzed reaction. This information enables us to propose a molecular mechanism explaining how long-chain aliphatic alcohols act as enantioselective inhibitors of this lipase in the resolution of 2-methyldecanoic acid. Long-chain aliphatic alcohols may coordinate to the acyl-binding tunnel of the C. rugosa lipase, thereby selectively inhibiting the turnover of the fast-reacting S-enantiomer, thus resulting in a lowered enantioselectlvity in the resolution.

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An all atom force field for simulations of proteins and nucleic acids

Cited by 3,470 publications

References 48 publications

Molecular dynamics simulations of alcohol dehydrogenase with a four‐ or five‐coordinate catalytic zinc ion

Molecular dynamics simulations of alcohol dehydrogenase with a four‐ or five‐coordinate catalytic zinc ion

NMR-Based, Molecular Dynamics- and Random Walk Molecular Mechanics-Supported Study of Conformational Aspects of a Carbohydrate Ligand (Galβ1-2Galβ1-R) for an Animal Galectin in the Free and in the Bound State

A structural basis for enantioselective inhibition of Candida rugosa lipase by long‐chain aliphatic alcohols

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