A new force field for molecular mechanical simulation of nucleic acids and proteins

Weiner, Scott J.; Kollman, Peter A.; Case, David A.; Singh, U. Chandra; Ghio, Caterina; Alagona, Giuliano; Profeta, Salvatore; Weiner, Paul K.

doi:10.1021/ja00315a051

Cited by 4,810 publications

(3,156 citation statements)

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“…This decision was also made on the background that the AutoDock program used does not contain fragmental volume or solvation parameters for DNA and insofar as the full free binding energy calculated by AutoDock had to be reduced to an intermolecular energy function based on the Weiner force field. 51 The freezing of ligand and receptor leads a Absolute energies and enthalpies in hartree, relative energies and enthaplies in kcal/mol, dipole moments in debye. R, U, or BS-U indicate whether restricted, unrestricted, or broken-symmetry unrestricted DFT was used.…”

Section: Methodsmentioning

confidence: 99%

Design of a New Warhead for the Natural Enediyne Dynemicin A. An Increase of Biological Activity

2008

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A concept for designing nontoxic enediyne-based antitumor drugs that was previously suggested (J. Am. Chem. Soc. 2000, 122, 8245) is converted into reality by merging amidines with the natural enediyne dynemicin A. The dynemicin-amidines (DADs) resulting from this combination are biologically not active because they form extremely labile singlet biradicals that can no longer abstract H from DNA. However, if protonated in the acidic environment of the tumor cell, they possess increased biological activity, as is reflected by a lowering of the activation enthalpy for the Bergman cyclization from 16.7 (dynemicin A) to 11-12 kcal/mol (DADs), kinetic stability of the singlet biradicals formed in the cyclization reaction, increased H abstraction ability of the singlet biradicals, and improved docking properties in the minor groove of the duplex 10-mer B-DNA sequence d(CTACTACTGG)‚d(CCAGTAGTAG) throughout the triggering and Bergman reactions. The implications and the consequences of using DADs to exploit the differences between normal and tumor cells and to design a nontoxic antitumor drugs are discussed.

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Section: Methodsmentioning

confidence: 99%

Design of a New Warhead for the Natural Enediyne Dynemicin A. An Increase of Biological Activity

2008

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“…20,22,23 Determination of the solvent-accessible surface area (ASA) values of amino acid residues causing a processing/transport defect in Pompe disease…”

Section: Determination Of Rmsd Values Of All Atoms In Mutant Human Acmentioning

confidence: 99%

Structural modeling of mutant α-glucosidases resulting in a processing/transport defect in Pompe disease

et al. 2009

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To elucidate the mechanism underlying transport and processing defects from the viewpoint of enzyme folding, we constructed three-dimensional models of human acid a-glucosidase encompassing 27 relevant amino acid substitutions by means of homology modeling. Then, we determined in each separate case the number of affected atoms, the root-mean-square distance value and the solvent-accessible surface area value. The analysis revealed that the amino acid substitutions causing a processing or transport defect responsible for Pompe disease were widely spread over all of the five domains comprising the acid a-glucosidase. They were distributed from the core to the surface of the enzyme molecule, and the predicted structural changes varied from large to very small. Among the structural changes, we paid particular attention to G377R and G483R. These two substitutions are predicted to cause electrostatic changes in neighboring small regions on the molecular surface. The quality control system of the endoplasmic reticulum apparently detects these very small structural changes and degrades the mutant enzyme precursor (G377R), but also the cellular sorting system might be misled by these minor changes whereby the precursor is secreted instead of being transported to lysosomes (G483R).

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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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A new force field for molecular mechanical simulation of nucleic acids and proteins

Cited by 4,810 publications

References 1 publication

Design of a New Warhead for the Natural Enediyne Dynemicin A. An Increase of Biological Activity

Design of a New Warhead for the Natural Enediyne Dynemicin A. An Increase of Biological Activity

Structural modeling of mutant α-glucosidases resulting in a processing/transport defect in Pompe disease

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

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