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  • 1
    Electronic Resource
    Electronic Resource
    Poisson-Boltzmann model studies of molecular electrostatic properties of the cAMP-dependent protein kinase (1999)
    Springer
    European biophysics journal 28 (1999), S. 457-467 
    Details
    ISSN: 1432-1017
    Keywords: Key words Poisson-Boltzmann model ; Protein kinases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Physics
    Notes: Abstract Protonation equilibria of residues important in the catalytic mechanism of a protein kinase were analyzed on the basis of the Poisson-Boltzmann electrostatic model along with a cluster-based treatment of the multiple titration state problem. Calculations were based upon crystallographic structures of the mammalian cAMP-dependent protein kinase, one representing the so called closed form of the enzyme and the other representing an open conformation. It was predicted that at pH 7 the preferred form of the phosphate group at the catalytically essential threonine 197 (P-Thr197) in the closed form is dianionic, whereas in the open form a monoanionic ionization state is preferred. This dianionic state of P-Thr197, in the closed form, is stabilized by interactions with ionizable residues His87, Arg165, and Lys189. Our calculations predict that the hydroxyl of the Ser residue in the peptide substrate is very difficult to ionize, both in the closed and open structures of the complex. Also, the supposed catalytic base, Asp166, does not seem to have a pK a appropriate to remove the hydroxyl group proton of the peptide substrate. However, when Ser of the peptide substrate is forced to remain ionized, the predicted pK a of Asp166 increases strongly, which suggests that the Asp residue is a likely candidate to attract the proton if the Ser residue becomes deprotonated, possibly during some structural change preceding formation of the transition state. Finally, in accord with suggestions made on the basis of the pH-dependence of kinase kinetics, our calculations predict that Glu230 and His87 are the residues responsible for the molecular pK a values of 6.2 and 8.5, observed in the experiment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002490050228
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  • 2
    Electronic Resource
    Electronic Resource
    Study of the Interactions between Neurophysin II and Dipeptide Ligand by Means of Molecular Dynamics (1995)
    Springer
    Journal of molecular modeling 1 (1995), S. 143-149 
    Details
    ISSN: 0948-5023
    Keywords: Keywords: neurophysin/dipeptide complex, peptide ligand interactions, association, molecular dynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The nonapeptide hormones oxytocin (OT) and vasopressin (VP), while transported in the posterior pituitary, are packaged into neurosecretory granules (NSG) in the form of high associates with disulfide-rich proteins known as neurophysin I (NPI) and neurophysin II (NPII), respectively. In the NSG, neurophysins serve as carrier proteins to the hormones, until the latter are dissociated upon secretion into blood. To shed more light on molecular self-recognition between NPs, and between NPs and their ligands, we have studied their molecular association, using as a starting point the recently published solid-state structure (Cα-trace) of the neurophysin II-dipeptide complex. Another purpose of this work was the development of reliable strategies for molecular modeling, that would utilize minimal structural information (like Cα-trace and/or structural homology) yet be useful for studies of protein/ligand interactions. An initial all-atom representation of the protein-peptide complex (2:2) was obtained by the conversion of the Cα-carbon trace deposited in the Brookhaven Protein Data Bank (file 1BN2), using the InsightII/Biopolymer modules from the suite of programs supplied by Biosym Technologies, San Diego. The free NPII homodimer was obtained by removal of the dipeptide ligands from the starting structures. Both associates, after initial immersion in water, were submitted to gradual (side chains first then all atoms) minimization of energy. Subsequently, they were thermally equilibrated and submitted to the molecular dynamics (AMBER 4.0) at 300K, until the total energy was stabilized. The structures, averaged over the last 20 ps of the dynamics, were compared with the starting Cα-trace and among themselves. The protein/ligand complex, simulated in water, compares favorably with the solid-state reference. An allosteric mechanism for the NPII dimer/ligand interaction is proposed and discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s008940050011
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  • 3
    Electronic Resource
    Electronic Resource
    A comparative study of time dependent quantum mechanical wave packet evolution methods (1992)
    College Park, Md. : American Institute of Physics (AIP)
    The Journal of Chemical Physics 96 (1992), S. 2077-2084 
    Details
    ISSN: 1089-7690
    Source: AIP Digital Archive
    Topics: Physics , Chemistry and Pharmacology
    Notes: We present a detailed comparison of the efficiency and accuracy of the second- and third-order split operator methods, a time dependent modified Cayley method, and the Chebychev polynomial expansion method for solving the time dependent Schrodinger equation in the one-dimensional double well potential energy function. We also examine the efficiency and accuracy of the split operator and modified Cayley methods for the imaginary time propagation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1063/1.462870
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  • 4
    Electronic Resource
    Electronic Resource
    Energy minimization and molecular dynamics studies of Asn-102 elastase (1987)
    Springer
    Journal of computer aided molecular design 1 (1987), S. 211-217 
    Details
    ISSN: 1573-4951
    Keywords: Molecular dynamics ; Energy minimization ; Serine proteases ; Enzyme mechanisms
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Four isomeric forms of the Asn-102 PPE (D 102 N mutant according to the emerging protocol, [Knowles, Science, 236 (1987) 1252–1258]) have been investigated using energy minimization (EM) and molecular dynamics (MD) techniques. MD simulation data for 175 ps are reported for each form (in total 700 ps for about 2500 atoms). The His-57 Nε-protonated forms are calculated to be more stable than the Nδ-protonated ones. The active site region of the most stable form is very similar to that found in the D102N rat trypsin enzyme [Craik et al., Science, 237 (1987) 909–913]. Conformations of the active sites and their hydrogen bond patterns are presented for each of these forms and are compared with the structure of the native enzyme active site. The pH dependent activity of the D102N derivative is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01677045
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  • 5
    Electronic Resource
    Electronic Resource
    Effect of water on the tautomeric equilibrium of 2-oxopyridine. A Monte Carlo simulation studyThis work was begun during one of the authors' (V.I.D.) stay in Poland in 1980. (1981)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 20 (1981), S. 359-364 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: With the empirical atom-atom potential the systems of one and three water molecules surrounding either the lactim or the lactam tautomer of 2-oxopyridine are simulated at temperatures of 198, 248, 298, and 348 K, using Monte Carlo techniques. The results show that the lactam form of the molecule is more stabilized by the water molecules than the lactim form by about 17-29 kJ/mol (4-7 kcal/mol), thus remaining in accordance with the conclusions inferred from experimental evidence.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560200732
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  • 6
    Electronic Resource
    Electronic Resource
    Ab initio calculations on the barrier to pseudorotation of model 2′-deoxyfuranose and 2′-deoxy-2′-fluorofuranose rings (1985)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 28 (1985), S. 517-523 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Model ring systems 2′-deoxy-2′-fluororibofuranose and deoxyribofuranose have been investigated using ab initio calculations with the 3-21G basis set. The energy barrier to pseudorotation between the N and S states has been evaluated for the three preferred orientations of the (3′)-OH group. Positions of the energy minima and the transition state have been optimized with respect to the (3′)-OH orientation. The barrier to pseudorotation of 2′-deoxy-2′-fluorofuranose is high and asymmetrical (ΔEN→S ≈ 20, ΔEN←S ≈ 8 kJ/mol), whereas the barrier of 2′-deoxyfuranose is lower and almost symmetrical (ΔE ≈ 11-12 kJ/mol). The results obtained show that the preferred configuration of the 2′-deoxy-2′-fluororibo-furanose (N state) is stabilized by an internal O(3′)-H…F interaction in accord with the crystallo-graphic data.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560280408
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  • 7
    Electronic Resource
    Electronic Resource
    Dynamic properties of the first enzymatic reaction steps of porcine pancreatic elastase. How rigid is the active site of the native enzyme? Molecular dynamics simulation (1990)
    New York : Wiley-Blackwell
    Biopolymers 30 (1990), S. 781-796 
    Details
    ISSN: 0006-3525
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Two molecular dynamics simulations (100 and 50 ps) of native porcine pancreatic elastase i.e., without bound substrate and with the active site hydrated by a dome of water (630 molecules) have been performed. Dynamical properties of the catalytic tetrad have been examined. While relative conformations of the Asp 102, His 57, and Ser 214 are rather stable in time, the side chain of Ser 195 undergoes several conformational changes. No preferences are observed for the formation of a hydrogen bond between the Oγ—H group (Ser 195) and nitrogen N∊ (His 57). A cluster of ordered water molecules effectively competes with the H—Oγ group (Ser 195) and thereby prevents the formation of this H bond, which is generally agreed to be crucial for catalysis.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/bip.360300713
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  • 8
    Electronic Resource
    Electronic Resource
    Lagrangian molecular dynamics using selected conformational degrees of freedom, with application to the pseudorotation dynamics of furanose rings (1994)
    New York : Wiley-Blackwell
    Biopolymers 34 (1994), S. 383-392 
    Details
    ISSN: 0006-3525
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Using internal conformational degrees of freedom for biopolymers as natural variables, and introducing a Lagrangian dynamics approach, one can simulate time-dependent processes over a much longer time scale than in classical Newtonian molecular dynamics (MD) techniques. Two factors contribute to this: a substantial reduction in the number of degrees of freedom and a very large increase in the size of the time step. We present the Lagrangian equations of motion for repuckering transitions in model furanose (F), ribose (R), and 2′-deoxyribose (dR) ring systems using the pseudorotation phase angle as the single dynamic variable. As in most Lagrangian analyses, the effective masses for the R and dRmodels are dependent on conformation, and we test the behavior of this variable mass (VM) model. Since the variation in effective mass is small, the VM model is compared with a simplified constant mass (CM) model, which is shown to be an excellent approximation. The equations of motion for the CM and VM models are integrated with the leapfrog and the iterative leapfrog algorithms, respectively. The Lagrangian dynamics approach reduces the number of degrees of freedom from about 40 to 1, and allows the use of time steps on the order of 20 fs, about an order of magnitude greater than is used in conventional MD simulations. © 1994 John Wiley & Sons, Inc.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/bip.360340310
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  • 9
    Electronic Resource
    Electronic Resource
    Thermodynamic cycle-perturbation study of the binding of trifluoroacetyl dipeptide anilide inhibitors with porcine pancreatic elastase (1990)
    New York : Wiley-Blackwell
    Biopolymers 30 (1990), S. 773-780 
    Details
    ISSN: 0006-3525
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The variety of results of crystallographic studies of the serine proteases complexed with isocoumnrin inhibitors presents a challenging problem to modeling methods and molecular energetics. Therefore, the thermodynamic cycle-perturbation technique has been used to study a model system of elastase and two peptidic inhibitors. Using the program AMBER, the technique correctly predicts changes of the binding constants for the trifluoroacetyl dipeptide inhibitors in comparison with available experimental (kinetic and crystallographic) data. However, the absolute values obtained are shown to be sensitive to the specific electrostatic interaction potential parameters used in the simulations. The reader and user are cautioned that thermodynamic cyle-perturbation results may be too optimistic by underestimating the accuracy of free energy values. This is especially a matter of concern for those cases where a direct comparison with experimental values is not possible, viz., (1) the simulation of binding of novel compounds, (2) structurally uncertain binding sites, or (3) structurally different binding modes. With our best 4-31G* ESP (electrostatic potential) charges we were able to reproduce experimentally determined free energy differences (ΔΔA) with an accuracy of about 1.5 kcal/mol. Dynamically induced structural changes in the binding site of elastase, and particularly changes in hydrogen-bond patterns of the binding site, are also reported.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/bip.360300712
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