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doi: 10.1002/(SICI)1096-987X(19961115)17:14<1587::AID-JCC1>3.0.CO;2-Hpmid: N/A
A recently proposed molecular dynamics method for estimating binding free energies is applied to the complexation of two charged benzamidine inhibitors with trypsin. The difficulties with calculations of absolute binding energies for charged molecules, associated with long‐range electrostatic contributions, are discussed and it is shown how to deal with these effectively. In particular, energetic effects caused by the trunction of dipole‐dipole interactions in the medium surrounding the charged ligand are examined and found to be significant. Calculations of the absolute binding energy for benzamidine using the free energy perturbation approach are also reported. These simulations illustrate the typical problems associated with annihilation transformations of molecules bound inside proteins. © 1996 by John Wiley & Sons, Inc.
Cummins, Peter L.; Gready, Jill E.
doi: 10.1002/(SICI)1096-987X(19961115)17:14<1598::AID-JCC2>3.0.CO;2-Gpmid: N/A
Molecular dynamics (MD) simulation methods have been used to study the active site of the ternary complex formed between avian dihydrofolate reductase (DHFR), NADPH cofactor, and the inhibitor 8‐methyl‐N5‐deazapterin in aqueous solution. Spherical shells of water molecules (initially at the bulk‐solvent density) are used to solvate the active site and the surrounding protein surface. Two models for treating the effects of the neglected bulk solvent are then considered. The tethered water (TW) model is characterized by the use of harmonic restraining potentials to tether the water molecules to their initial (bulk solvent) positions; whereas, in the capped water (CW) model, water molecules are prevented from escaping from the solvent shell by the use of half‐harmonic potentials, but otherwise their motions within the solvation shell are unrestrained. As measured by overall rms differences between coordinates, the distribution of solvent molecules in the active‐site region, and the numbers of hydrogen bonds, the TW model compares favorably with the CW model but requires far fewer water molecules, i.e., relatively small solvent shells. The smaller shells of unrestrained water (CW model) gave rise to a distortion in the orientation of the side chain of the active‐site residue Tyr‐31, whereas no such distortion was apparent in the TW model or for the larger solvent shells in the CW model. A value for the force constant of 0.005 kcal/mol/Å2 for the tethering potential (Solmajer and Mehler, Int. J. Quant. Chem., 44, 291 (1992)) gave satisfactory results for DHFR, although we found that distance‐dependent dielectric functions were unable to reproduce accurately the effects of the explicit water models. The free‐energy change for the mutation of 8‐methyl‐N5‐deazapterin to 8‐methylpterin was computed using both nonsolvated and solvated models. The solvated models gave free energy differences about 1 kcal/mol lower than for nonsolvated models, but the differences between solvated models was much less than 1 kcal/mol. Overall, the calculated differences in thermodynamic stability of the deazapterin and pterin complexes are in fair agreement with experiment, i.e., a small binding differential is predicted. © 1996 by John Wiley & Sons, Inc.
doi: 10.1002/(SICI)1096-987X(19961115)17:14<1612::AID-JCC3>3.0.CO;2-Opmid: N/A
A new algorithm involving the calculation of the solid angle of a molecule about a point as a measure of steric size has been developed. The algorithm calculates the total solid angle in a stepwise fashion, summing all regions of individual atom solid angles and overlapped atoms, taking into account all orders of possible overlap of multiple atoms. The results for several molecular fragments have been compared to previous solid and cone angle calculations and improved correlations were observed. © 1996 by John Wiley & Sons, Inc.
doi: 10.1002/(SICI)1096-987X(19961115)17:14<1624::AID-JCC4>3.0.CO;2-Npmid: N/A
Two typical series of C60 embedded complexes (X@C60) (X = Li, Na, K, Rb, Cs; F, Cl, Br, I) have been chosen to study as prototypes, in which the Buckingham potential (exp‐6‐1) function was applied to calculating the interactions of the atom pairs. The potential parameters are obtained from related crystals by the simulations using molecular mechanics methods. To utilize the symmetry of the potential field in C60, the calculation is carried out along five typical radial directions. The computational results show that the interaction between the embedded atom and the C60 cage is not purely electrostatic. The repulsive energy, Erep, accounts for from 0.2% to 6.6% (for the alkali series), and from 1.5% to 58% (for the halogen series); the dispersive energy Edis accounts for from 1.2% to 6.5% (for the alkali series), and from 2.2% to 42% (for the halogen series); and the electrostatic energy, Ees, accounts for 99% to 87% (for the alkali series) and from 96% to 0% (for the halogen series) when the embedded atom is put at the center of the cage. Erep reaches up to 8% ∼ 35% (alkali), and 16% ∼ 704% (halogen); Edis up to 4% ∼ 16% (alkali) and 7% ∼ 26% (halogen); and Ees falls down to about 88% ∼ 49% (alkali), and 96% ∼ 0% (halogen), when the embedded atom deviates 1.8 A from the cage center. The total interactions, Einter, are all attractive for X (X = Li, Na, K, Rb, Cs; F. Cl, Br), but repulsive for the I atom. It is shown that the potential field in the C60 cage has nearly spherical symmetry in an area with a radius of 1.8 Å around the cage center. The same kinds of interactions for the atoms in the two individual series are compared, and some variation rules are obtained. For (Li@C60), the minimum energy equilibrium point deviates from the center by about 0.5 Å. © 1996 by John Wiley & Sons, Inc.
Antosiewicz, Jan; Briggs, James M.; Elcock, Adrian H.; Gilson, Michael K.; McCammon, J. Andrew
doi: 10.1002/(SICI)1096-987X(19961115)17:14<1633::AID-JCC5>3.0.CO;2-Mpmid: N/A
A convenient computational approach for the calculation of the p Kas of ionizable groups in a protein is described. The method uses detailed models of the charges in both the neutral and ionized form of each ionizable group. A full derivation of the theoretical framework is presented, as are details of its implementation in the UHBD program. Application to four proteins whose crystal structures are known shows that the detailed charge model improves agreement with experimentally determined pKas when a low protein dielectric constant is assumed, relative to the results with a simpler single‐site ionization model. It is also found that use of the detailed charge model increases the sensitivity of the computed pKas to the details of proton placement. © 1996 by John Wiley & Sons, Inc.
JELSKI, DANIEL A.; HALEY, RANDALL H.; BOWMAN, JOEL M.
doi: 10.1002/(SICI)1096-987X(19961115)17:14<1645::AID-JCC6>3.0.CO;2-Lpmid: N/A
A recently developed, general computer program that performs vibrational self‐consistent field (VSCF) calculations for large molecules is described. The program, which we refer to as VSCF―95, requires as its only input a force field in mass‐scaled normal coordinates. Currently, it is limited to a maximum of 200 normal modes, and the force field is limited to coupling terms involving a maximum of six normal modes, with a maximum order of six in any normal mode. As output the program returns VSCF energies for specified quantum states. We illustrate the code with two new applications. The first is to HCO, for which we use a full sixth‐order force field. The second is to a model of the fullerene, C60, for which we have calculated a 75,731‐term force field, which includes all anharmonic terms up to fifth order, and all two‐mode coupling terms up to fourth order. © 1996 by John Wiley & Sons, Inc.
GRANT, J. A.; GALLARDO, M. A.; PICKUP, B. T.
doi: 10.1002/(SICI)1096-987X(19961115)17:14<1653::AID-JCC7>3.0.CO;2-Kpmid: N/A
A Gaussian description of molecular shape is used to compare the shapes of two molecules by analytically optimizing their volume intersection. The method is applied to predict the relative orientation of ligand series binding to the proteins, thrombin, HIV protease, and thermolysin. The method is also used to quantify the degree of chirality of asymmetric molecules and to investigate the chirality of biphenyl and the amino acids. The shape comparison method uses the newly described shape multipoles that can also be used to describe the inherent shape of molecules. Some results of calculated shape quadrupoles are given for the ligands used in this work. © 1996 by John Wiley & Sons, Inc.
doi: 10.1002/(SICI)1096-987X(19961115)17:14<1667::AID-JCC8>3.0.CO;2-Jpmid: N/A
We present a new side‐chain prediction method based on energy minimization using a Hopfield network, focusing on the buried residues of proteins. In this method, the network is composed of automata assigned to each rotamer to restrict side‐chain conformational space. We reproduced a rotamer library that enabled us to more widely cover the space for side‐chain conformations than those previously produced. The accuracy of the side‐chain modeling was estimated by three standards: root mean square deviations (rmsds) between the modeled and the crystal structures, the percentages of correctly predicted side‐chain torsion angles, and the percentages of correctly predicted hydrogen bonds. The average rmsd for buried side chains of 21 proteins was 1.10 Å. The value was almost always improved relative to the previous works. The percentage of side‐chain X1 angles for buried residues was 87.3%. By considering the hydrogen bond energy, the average percentage of correctly predicted hydrogen bonds rose from 33% without hydrogen bond energy to 52% with the bond energy. We applied this method to homology modeling, where the protein backbone used to predict side‐chain conformations deviates from the correct conformation, and could predict side‐chain conformations as correctly as those using the correct backbones. © 1996 by John Wiley & Sons, Inc.
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