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  • Computational Chemistry and Molecular Modeling  (24)
  • Theoretical, Physical and Computational Chemistry  (5)
  • molecular dynamics  (5)
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  • 1
    Electronic Resource
    Electronic Resource
    The application of three approximate free energy calculations methods to structure based ligand design: Trypsin and its complex with inhibitors (1998)
    Springer
    Journal of computer aided molecular design 12 (1998), S. 215-227 
    Details
    ISSN: 1573-4951
    Keywords: free energy calculations ; ligand design ; molecular dynamics ; Pictorial Representation of Free Energy Changes (PROFEC)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Three approximate free energy calculation methods are examined and applied to an example ligand design problem. The first of the methods uses a single simulation to estimate the relative binding free energies for related ligands that are not simulated. The second method is similar, except that it uses only first derivatives of free energy with respect to atomic parameters (most often charge, van der Waals equilibrium distance, and van der Waals well depth) to calculate free energy differences. The last method PROFEC (Pictorial Representation of Free Energy Components), generates contour maps that show how binding free energy changes when additional particles are added near the ligand. These three methods are applied to a benzamidine/trypsin complex. They each reproduce the general trends in the binding free energies, indicating that they might be useful for suggesting how ligands could be modified to improve binding and, consequently, useful in structure-based drug design.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007905722422
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  • 2
    Electronic Resource
    Electronic Resource
    Predicting relative binding affinities of non-peptide HIV protease inhibitors with free energy perturbation calculations (1999)
    Springer
    Journal of computer aided molecular design 13 (1999), S. 109-121 
    Details
    ISSN: 1573-4951
    Keywords: free energy calculations ; molecular dynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The relative binding free energies in HIV protease of haloperidol thioketal (THK) and three of its derivatives were examined with free energy calculations. THK is a weak inhibitor (IC50 = 15 μM) for which two cocrystal structures with HIV type 1 proteases have been solved [Rutenber, E. et al., J. Biol. Chem., 268 (1993) 15343]. A THK derivative with a phenyl group on C2 of the piperidine ring was expected to be a poor inhibitor based on experiments with haloperidol ketal and its 2- phenyl derivative (Caldera, P., personal communication). Our calculations predict that a 5-phenyl THK derivative, suggested based on examination of the crystal structure, will bind significantly better than THK. Although there are large error bars as estimated from hysteresis, the calculations predict that the 5-phenyl substituent is clearly favored over the 2-phenyl derivative as well as the parent compound. The unfavorable free energies of solvation of both phenyl THK derivatives relative to the parent compound contributed to their predicted binding free energies. In a third simulation, the change in binding free energy for 5-benzyl THK relative to THK was calculated. Although this derivative has a lower free energy in the protein, its decreased free energy of solvation increases the predicted ΔΔG(bind) to the same range as that of the 2-phenyl derivative.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008044721715
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  • 3
    Electronic Resource
    Electronic Resource
    Restrained molecular dynamics of solvated duplex DNA using the particle mesh Ewald method (1999)
    Springer
    Journal of biomolecular NMR 13 (1999), S. 119-131 
    Details
    ISSN: 1573-5001
    Keywords: DNA structure ; molecular dynamics ; particle mesh Ewald ; solvated refinement
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Restrained and unrestrained aqueous solution molecular dynamics simulations applying the particle mesh Ewald (PME) method to DNA duplex structures previously determined via in vacuo restrained molecular dynamics with NMR-derived restraints are reported. Without experimental restraints, the DNA decamer, d(CATTTGCATC)⋅d(GATGCAAATG) and trisdecamer, d(AGCTTGCCTTGAG)⋅d(CTCAAGGCAAGCT), structures are stable on the nanosecond time scale and adopt conformations in the B-DNA family. These free DNA simulations exhibit behavior characteristic of PME simulations previously performed on DNA sequences, including a low helical twist, frequent sugar pucker transitions, BI- BII(ε−ζ) transitions and coupled crankshaft (α−γ) motion. Refinement protocols similar to the original in vacuo restrained molecular dynamics (RMD) refinements but in aqueous solution using the Cornell et al. force field [Cornell et al. (1995) J. Am. Chem. Soc., 117, 5179–5197] and a particle mesh Ewald treatment produce structures which fit the restraints very well and are very similar to the original in vacuo NMR structure, except for a significant difference in the average helical twist. Figures of merit for the average structure found in the RMD PME decamer simulations in solution are equivalent to the original in vacuo NMR structure while the figures of merit for the free MD simulations are significantly higher. The free MD simulations with the PME method, however, lead to some sequence-dependent structural features in common with the NMR structures, unlike free MD calculations with earlier force fields and protocols. There is some suggestion that the improved handling of electrostatics by PME improves long-range structural aspects which are not well defined by the short-range nature of NMR restraints.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008353423074
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  • 4
    Electronic Resource
    Electronic Resource
    Application of the quantum mechanics and free energy perturbation methods to study molecular processes (1987)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 32 (1987), S. 65-74 
    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: The molecular dynamics free energy perturbation method was applied to study the solvation effect on the tautomeric equilibria in water solution as well as association of the nucleic acid base pairs in water solution and in vacuo. Tautomerization energies in vacuo calculated by the ab initio SCF-HF method differed from experiment by 1-2 kcal/mol, even if geometry optimization was performed and MP2 correlation energy calculated at 6-31G* basis set was added.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560320811
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  • 5
    Electronic Resource
    Electronic Resource
    Absolute and relative binding free energy calculations of the interaction of biotin and its analogs with streptavidin using molecular dynamics/free energy perturbation approaches (1993)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 16 (1993), S. 226-245 
    Details
    ISSN: 0887-3585
    Keywords: molecular dynamics ; biotin ; avidin ; free energy calculations ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We present calculations of the absolute and relative binding free energies of complexation of streptavidin with biotin and its analogsby means of a thermodynamic free energy perturbation method implemented with molecular dynamics. Using the recently solved crystal structure of the streptavidin-biotin complex, biotin was mutated into a dummy molecule as well as thiobiotin and iminobiotin both in the protein and insolution. The calculated absolute binding free energy was dependent on the simulation model used. Encouragingly, the “best models” provided a reasonable semiquantitative reproduction (-20 to -22 kcal/mol) of the experimental free energy (-18.3 kcal/ mol). Furthermore, the calculated results give clear insights into the binding nature of the protein-ligand complex, showing that the van der Waals energy dominates the electrostatic and hydrogen bonding energies in thebinding of biotin by streptavidin. Specifically, the mutation of biotin into a dummy molecule in solution has a ΔG (van der Waals) ∼ -4 kcal/mol, due to the cancellation of dispersion and repulsion “cavity” effects. On the other hand, in the protein, a very small free energy price must be paid to create a cavity since one already exists and the mutation of biotin into a dummy molecule has a ΔG (van der Waals) ∼ 15 kcal/mol. These results are also consistent with the interpretation that the entropy increase to be expected from hydrophobic interactions from desolvation of biotin is counterbalanced by a decrease in entropy accompanying the formationof buried hydrogen bonds, which have been derived from the apparentlyconflicting experimental data. They provide an alternative interpretationofthe reason for the extremely high affinity of the biotin-streptavidin interaction than that recently proposed by Weber et al. (J. Am. Chem. Soc. 114:3197, 1992). In the case of the relative binding freeenergies, the calculated values of 3.8 ± 0.6 and 7.2 ± 0.6 kcal/mol compare well with the experimental values of 3.6 and 6.2 kcal/mol for the perturbation of biotin to thiobiotin and iminobiotin, respectively in the related protein avidin. The calculations indicate that desolvation of the ligand is important in understanding the relative affinity of the ligands with the protein. The above successful simulations suggestthat the molecular dynamics/free energy perturbation method is useful for understanding the energetic features affecting the binding between proteins and ligands, since it is generally difficult to determine these factors unambiguously by experiment. This set of studies provide a textbook example of the key elements of protein-ligand recognition: the electrostatic free energy dominates the relative affinities, the van der Waals free energy dominates the absolute free energy; the free energy of desolvation is a key to why iminobiotin is so much more weakly bound than biotin and the free energy of binding explains why thiobiotin is so weakly bound relative to biotin. © 1993 Wiley-Liss, Inc.
    Additional Material: 11 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340160303
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  • 6
    Electronic Resource
    Electronic Resource
    Molecular dynamics characterization of the active cavity of carboxypeptidase A and some of its inhibitor adducts (1992)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 13 (1992), S. 288-305 
    Details
    ISSN: 0887-3585
    Keywords: molecular dynamics ; catalysis carboxypeptidase ; ligand binding ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Molecular dynamics (MD) calculations have been performed on carboxypeptidase A and on its adducts with inhibitors, such as d-phenylalanine (dPhe) and acetate. The catalytically essential zinc ion present in the protein was explicitly included in all the simulations. The simulation was carried out over a sphere of 15 Å centered on the zinc ion. The crystallographic water molecules were explicitly taken into account; then the protein was solvated with a 18 Å sphere of water molecules. MD calculations were carried out for 45-60 ps. There is no large deviation from the available X-ray structures of native and the dPhe adduct for the MD stuctures. Average MD structures were calculated starting from the X-ray structure of the dPhe adduct, and, from a structure obtained by docking the inhibitor in the native structure. Comparison between these two structures and with that of the native protein shows that some of the key variations produced by inhibitor binding are reproduced by MD calculations. Addition of acetate induces structural changes relevant for the understanding of the interaction network in the active cavity. The structural variations induced by different inhibitors are examined. The effects of these interactions on the catalytic mechanism and on the binding of substrate are discussed. © 1992 Wiley-Liss, Inc.
    Additional Material: 12 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340130403
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  • 7
    Electronic Resource
    Electronic Resource
    The reaction of n-butyllithium with benzoic acid: is nucleophilic addition competitive with deprotonation?Dedicated to Frederick G. Bordwell for his many and continuing contributions to physical organic chemistry (1997)
    Chichester : Wiley-Blackwell
    Journal of Physical Organic Chemistry 10 (1997), S. 537-541 
    Details
    ISSN: 0894-3230
    Keywords: n-Butyllithium ; benzoic acid ; nucleophilic addition ; deprotonation ; Chemistry ; Theoretical, Physical and Computational Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: ---An evaluation of a branching vs sequential mechanism for the reaction of benzoic acid with n-butyllithium favors the latter. © 1997 John Wiley & Sons, Ltd.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Free energy perturbation calculations on models of active sites: Applications to adenosine deaminase inhibitors (1990)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Computational Chemistry 11 (1990), S. 994-1002 
    Details
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: Free energy perturbation calculations were performed to determine the free energy of binding associated with the presence of perhaps an unusual hydroxyl group in the transition state analog of nebularine, an inhibitor of the enzyme adenosine deaminase. The presence of a single hydroxyl group in this inhibitor has been found to contribute -9.8 kcal/mol to the free energy of binding, with a 108-fold increase in the binding affinity by the enzyme. In this work, we calculate the difference in solvation free energy for the 1,6-dihydropurine complex versus that of the 6-hydroxyl-1,6-dihydropurine complex to determine if this marked increase in binding affinity is attributed to an unusually hydrophobic hydroxyl group. The calculated ΔG associated for the solvation free energy is -11.8 kcal/mol. This large change in the solvation free energy suggests that this hydroxyl is instead unusually hydrophilic and that the difference in free energy of interaction for the two inhibitors to the enzyme must be at least ca. 20 kcal/mol. Although the crystal structure for adenosine deaminase is currently not known, we attempt to mimic the nature of the active site by constructing models which simulate the enzyme-inhibitor complex. We present a first attempt at determining the change in free energy of binding for a system in which structural data for the enzyme is incomplete. To do this, we construct what we believe is a minimal model of the binding between adenosine deaminase and an inhibitor. The active site is simulated as a single charged carboxyl group which can form a hydrogen bond with the hydroxyl group of the analog. Two different carboxyl anion models are used. In the first model, the association is modeled between an acetic acid anion and the modified inhibitor. The second model consists of a hydrophobic amino acid pocket with an interior Glu residue in the active site. From these models we calculate the change in free energy of association and the overall change in free energy of binding. We calculate the free energies of interaction both in the absence and presence of water. We conclude from this that the presence of a single suitably placed-CO-2 group probably cannot explain the binding effect of the-OH group and that additional interactions will be found in the adenosine deaminase active site.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcc.540110811
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  • 9
    Electronic Resource
    Electronic Resource
    Comparison of ab initio, semiempirical, and molecular mechanics calculations for the conformational analysis of ring systems (1992)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Computational Chemistry 13 (1992), S. 525-532 
    Details
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: The potential energy surfaces of four cyclic alkanes have been examined using molecular mechanics, semiempirical, and ab initio methods to determine if they produce mutually consistent results and investigate the source of any errors between the methods. The C5 — C8 cyclic alkanes were chosen since these structures present a finite set of conformations and transition-state geometries and are still within the computational time and memory limits of the quantum mechanical approaches. We also examined several conformations of 1,2-dideoxyribose to determine the effect of heteroatoms on the results for the 5-membered ring. The molecular mechanics and ab initio calculations are consistent in the relative energies and geometries determined for the conformers of all ring systems. While the semiempirical calculations yielded geometries consistent with the other methods (except for 5-membered rings), the relative energies often deviated substantially. A decomposition analysis of the semiempirical and molecular mechanics energies revealed that the disparities are mainly due to errors in the 1-center energies of the semiempirical calculations. The 2-center bonding and nonbonding energies followed reasonable trends for the conformers. The core-repulsion function, however, is suspected of producing anomalies. A minimum in the attractive Gaussian of this term at 2.1 Å for H—H interactions partly explains the propensity of the 5-membered rings to optimize to near planarity (decreasing 1,2-diaxial hydrogen distances to 2.3 Å) and the underestimation of the relative energy of the boat structure of cyclohexane.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcc.540130413
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  • 10
    Electronic Resource
    Electronic Resource
    AMBERCUBE MD, parallelization of Amber's molecular dynamics module for distributed-memory hypercube computers (1993)
    New York, NY [u.a.] : Wiley-Blackwell
    Journal of Computational Chemistry 14 (1993), S. 312-329 
    Details
    ISSN: 0192-8651
    Keywords: Computational Chemistry and Molecular Modeling ; Biochemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Computer Science
    Notes: A fully functional parallel version of the molecular dynamics (MD) module of AMBER3a has been implemented. Procedures parallelized include the calculation of the long-range nonbonded Coulomb and Lennard-Jones interactions, generation of the pairlist, intramolecular bond, angle, dihedral, 1-4 nonbonded interaction terms, coordinate restraints, and the SHAKE bond constraint algorithm. As far as we can determine, this is the first published description where a distributed-memory MIMD parallel implementation of the SHAKE algorithm has been designed to treat not only hydrogen-containing bonds but also all heavy-atom bonds, and where “shaken” crosslinks are supported as well. We discuss the subtasking and partitioning of an MD time-step, load balancing the nonbonded evaluations, describe in algorithmic detail how parallelization of SHAKE was accomplished, and present speedup, efficiency, and benchmarking results achieved when this hypercube adaptation of the MD module AMBER was applied to several variant molecular systems. Results are presented for speedup and efficiency obtained on the nCUBE machine, using up to 128 processors, as well as benchmarks for performance comparisons with the CRAY YMP and FPS522 vector machines. © 1993 John Wiley & Sons, Inc.
    Additional Material: 10 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcc.540140307
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