David W. Deerfield

Adventures in Improving the Scaling and Accuracy of a Parallel Molecular Dynamics Program

We report our work to parallelize the Particle Mesh Ewald (PME) method to compute the long-range electrostatic interactions in the molecular dynamics program AMBER and to extend the scalability of the PME method to hundreds of processors.

Parallel ab initio and molecular mechanics investigation of polycoordinated Zn(II) complexes with model hard and soft ligands: Variations of binding energy and of its components with number and charges of ligands

In this study we compare the binding energies of polycoordinated complexes of Zn2+ within cavities composed of model “hard” (H2O, OH−) or “soft” (CH3SH, CH3S−) ligands. Ab initio supermolecule computations are performed at the HF and MP2 levels using extended basis sets to determine the binding energies and their components as a function of: the number of ligands, ranging from three to six; the net charge of the cavity; and the “hard” versus “soft” character of the ligands. These ab initio computations are used to test the reliability of the SIBFA molecular mechanics procedure, originally formulated and calibrated on the basis of ab initio computations, for such charged systems. The SIBFA intermolecular interaction energies match the corresponding ab initio values using a coreless effective potential split‐valence basis set with a relative error of ≤3%. Extensions to binuclear Zn2+ complexes, such as those that occur in the Zn‐binding sites of Gal4 and β‐lactamase proteins, are performed to test the applicability of the methodology for such systems.

PM3-compatible zinc parameters optimized for metalloenzyme active sites

Recent studies have shown that semiempirical methods (e.g., PM3 and AM1) for zinc‐containing compounds are unreliable for modeling structures containing zinc ions with ligand environments similar to those observed in zinc metalloenzymes. To correct these deficiencies a reparameterization of zinc at the PM3 level was undertaken. In this effort we included frequency corrected B3LYP/6‐311G* zinc metalloenzyme ligand environments along with previously utilized experimental data. Average errors for the heats of formation have been reduced from 46.9 kcal/mol (PM3) to 14.2 kcal/mol for this new parameter set, termed ZnB for “Zinc, Biological.” In addition, the new parameter sets predict geometries for the Bacillus fragilis active site model and other zinc metalloenzyme mimics that are qualitatively in agreement with high‐level ab initio results, something existing parameter sets failed to do.

Molecular recognition of aldehydes by aldehyde dehydrogenase and mechanism of nucleophile activation

Experimental structural data on the state of substrates bound to class 3 Aldehyde Dehydrogenases (ALDH3A1) is currently unknown. We have utilized molecular mechanics (MM) simulations, in conjunction with new force field parameters for aldehydes, to study the atomic details of benzaldehyde binding to ALDH3A1. Our results indicate that while the nucleophilic Cys243 must be in the neutral state to form what are commonly called near‐attack conformers (NACs), these structures do not correlate with increased complexation energy calculated with the MM‐Generalized Born Molecular Volume (GBMV) method. The negatively charged Cys243 (thiolate form) of ALDH3A1 also binds benzaldehyde in a stable conformation but in this complex the sulfur of Cys243 is oriented away from benzaldehyde yet yields the most favorable MM‐GBMV complexation energy. The identity of the general base, Glu209 or Glu333, in ALDHs remains uncertain. The MM simulations reveal structural and possible functional roles for both Glu209 and Glu333. Structures from the MM simulations that would support either glutamate residue as the general base were further examined with Hybrid Quantum Mechanical (QM)/MM simulations. These simulations show that, with the PM3/OPLS potential, Glu209 must go through a step‐wise mechanism to activate Cys243 through an intervening water molecule while Glu333 can go through a more favorable concerted mechanism for the same activation process. Proteins 2004.

Relative affinity of Ca(II) and Mg(II) ions for human and bovine prothrombin and fragment 1

Equilibrium dialysis results are presented for Ca(II) and Mg(II) ion binding to human and bovine prothrombin and fragment 1. Ca(II) ions bind cooperatively, Mg(II) does not.

Initial catalytic events in class 3 aldehyde dehydrogenase: MM and QM/MM simulations

A novel enzyme mechanism has been predicted by computer simulations for formation of the thiohemiacetal intermediate in the rat ALDH3A1 enzyme. We used molecular mechanics simulations to study the atomic details of substrate binding and quantum mechanical/molecular mechanical methods to study the Cys-243 thiolate attack on benzaldehyde (BA) substrate. BA was found to produce more reactive conformers when aligned for formation of the tetrahedral thiohemiacetal in the R-configuration. In addition, the sulfhydryl proton was seen to be important for initial binding of the substrate. Finally, the free energy differences between forming a thiohemiacetal oxyanion intermediate versus forming a neutral thiohemiacetal intermediate where a proton is donated to the intermediate from the surroundings strongly favor the latter. Our results suggest that the proton donor is the amide proton from the Cys-243 backbone supported by interactions with Lys-235.

An ab initio quantum mechanical study of thioesters

Abstract Model thioesters have been studied using ab initio quantum mechanical computations to determine the geometry and difference in energy for inherent rotamers. The Z isomer of the thioester is found to be 4.9 kcal mol −1 ( Δ 0 298 more stable than the E isomer, with the barrier for rotation ( Z → E ) 10.1 kcal mol −1 ( ΔG ‡ 298 ). Parameters for molecular mechanics computations are provided.

Enol and deprotonated forms of acetic and malonic acid

Abstract We have determined the structure and relative energies for various enol and deprotonated forms of acetic and malonic acid using several basis sets without and with electron correlation. At the MP2/6-31 + + G ∗∗ level, the corrected (for zero point energy and to 298K) energies for the deprotonation of acetic acid are −344.7 (0 → −1) and −499.0 (−1 → −2) kcal mol −1 with the enol(ate) form being 30.8 (0) and 26.4 (−1) kcal mol −1 less stable than the carboxylate form. At the MP2/6-31 + + G ∗∗ level, the corrected (for zero point energy and to 298K) energies for the deprotonation of malonic acid are −332.1 (0 → −1), −425.3 (−1 → −2) and −574.9 (−2 → −3) kcal mol −1 with the deprotonated on carbon forms 9.8 (−1) and 31.2 (−2) kcal mol −1 less stable than the corresponding carboxylate (deprotonated on oxygen) forms.

Mathematically Complete Nucleotide and Protein Sequence Searching Using Ssearch

In this unit a protocol is described for predicting the structure of simple transmembrane a‐helical bundles. The protocol is based on a global molecular dynamics search (GMDS) of the configuration space of the helical bundle, yielding several candidate structures. The correct structure among these candidates is selected using information from silent amino acid substitutions, employing the premise that only the correct structure must (by definition) accept all of the silent amino acid substitutions. Thus, the correct structure is found by repeating the GMDS for several close homologs and selecting the structure that persists in all of the trials.

Structure and relative acidity for a model zinc finger

Abstract We have performed ab initio computations examining the structure and relative acidity for a model (Zn(II)–(H 2 S) 2 (Imidazole) 2 ) for the zinc finger binding site. All possible deprotonated forms were studied. The lowest energy complex was a mono-deprotonated form (Zn(II)–(H 2 S)(HS − )(Imidazole) 2 ). In addition, we found that a triply deprotonated form (Zn(II)–(H 2 S)–(HS − )(deprotonated imidazole) 2 ) rearranges to unique but not unexpected forms.