Jeffrey D. Evanseck

All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins †

New protein parameters are reported for the all-atom empirical energy function in the CHARMM program. The parameter evaluation was based on a self-consistent approach designed to achieve a balance between the internal (bonding) and interaction (nonbonding) terms of the force field and among the solvent-solvent, solvent-solute, and solute-solute interactions. Optimization of the internal parameters used experimental gas-phase geometries, vibrational spectra, and torsional energy surfaces supplemented with ab initio results. The peptide backbone bonding parameters were optimized with respect to data for N-methylacetamide and the alanine dipeptide. The interaction parameters, particularly the atomic charges, were determined by fitting ab initio interaction energies and geometries of complexes between water and model compounds that represented the backbone and the various side chains. In addition, dipole moments, experimental heats and free energies of vaporization, solvation and sublimation, molecular volumes, and crystal pressures and structures were used in the optimization. The resulting protein parameters were tested by applying them to noncyclic tripeptide crystals, cyclic peptide crystals, and the proteins crambin, bovine pancreatic trypsin inhibitor, and carbonmonoxy myoglobin in vacuo and in crystals. A detailed analysis of the relationship between the alanine dipeptide potential energy surface and calculated protein φ, χ angles was made and used in optimizing the peptide group torsional parameters. The results demonstrate that use of ab initio structural and energetic data by themselves are not sufficient to obtain an adequate backbone representation for peptides and proteins in solution and in crystals. Extensive comparisons between molecular dynamics simulations and experimental data for polypeptides and proteins were performed for both structural and dynamic properties. Energy minimization and dynamics simulations for crystals demonstrate that the latter are needed to obtain meaningful comparisons with experimental crystal structures. The presented parameters, in combination with the previously published CHARMM all-atom parameters for nucleic acids and lipids, provide a consistent set for condensed-phase simulations of a wide variety of molecules of biological interest.

Influence of the heme pocket conformation on the structure and vibrations of the Fe-CO bond in myoglobin: a QM/MM density functional study.

The influence of the distal pocket conformation on the structure and vibrations of the heme-CO bond in carbonmonoxy myoglobin (MbCO) is investigated by means of hybrid QM/MM calculations based on density functional theory combined with a classical force field. It is shown that the heme-CO structure (QM treated) is quite rigid and not influenced by the distal pocket conformation (MM treated). This excludes any relation between FeCO distortions and the different CO absorptions observed in the infrared spectra of MbCO (A states). In contrast, both the CO stretch frequency and the strength of the CO...His64 interaction are very dependent on the orientation and tautomerization state of His64. Our calculations indicate that the CO...N(epsilon) type of approach does not contribute to the A states, whereas the CO...H-N(epsilon) interaction is the origin of the A(1) and A(3) states, the His64 residue being protonated at N(epsilon). The strength of the CO...His64 interaction is quantified, in comparison with the analogous O(2)...His64 interaction and with the observed changes in the CO stretch frequency. Additional aspects of the CO...His64 interaction and its biological implications are discussed.

Solvent effects in molecular recognition

Synthetic cyclophane hosts form stable and highly structured inclusion complexes with organic molecules in aqueous solutions. The solution geometries of these complexes are determined in a conformational analysis using Monte Car10 methods. Solvation-desolvation processes are a central factor in determining the stability of apolar inclusion complexes. The tight binding of small aromatic solutes in water is entropically unfavorable and is predominantly enthalpy-driven. A large part of the favorable enthalpy term for strong complexation in water results from its specific contributions. Electron donor-acceptor interactions stabilize complexes between electron-rich cyclophane hosts and electron-deficient aromatic substrates; however, they may be masked by specific solvation effects. Computer liquid phase simulations are undertaken to evaluate at a microscopic level the origin of such solvation effects. The progress in the modeling studies is described. Apolar complexation also occurs in organic solvents. Solvents like 2,2,2-trifluoroethanol and ethylene glycol come close to water in their ability to promote apolar complexation. Binding strength decreases from water to polar protic to dipolar aprotic and to apolar solvents. Complexation strength in solvents of all polarity including water and in binary aqueous solvent mixtures is predictable according to a linear free energy relationship between the complexation free energy and the empirical solvent polarity parameter ET(30).

Elucidation of Rate Variations for a Diels-Alder Reaction in Ionic Liquids from QM/MM Simulations.

The impact of acidic and basic ionic liquid 1-ethyl-3-methylimidazolium chloride (EMIC) melts upon cyclopentadiene and methyl acrylate Diels-Alder reaction rates has been investigated using QM/MM calculations. The ability of the ionic liquid to act as a hydrogen bond donor (cation effect), moderated by its hydrogen bond accepting ability (anion effect), has been proposed previously to explain observed endo/exo ratios. However, the molecular factors that endow ionic liquids with their rate enhancing potential remain unknown. New OPLS-AA force field parameters in conjunction with potentials of mean force (PMF) derived from free energy perturbation calculations in Monte Carlo simulations (MC/FEP) are used to compute activation energies. QM/MM simulations using a periodic box of ions reproduce relative rate enhancements for the EMIC melts compared to water and 1-chlorobutane that reproduce kinetic experiments. Solute-solvent interactions in acidic and basic ionic liquid melts have been analyzed at key stationary points along the reaction coordinate. The reaction rate was found to be greater in the acidic rather than the basic melt due to less-dominant ion-pairing in the acidic melt, enabling the EMI cation to better coordinate to the dienophile at the transition state. The simulations suggest that the hydrogen on C2 of the EMI cation does not contribute to stabilization of the transition state, as previously believed, and the interactions with the more sterically exposed hydrogens on C4 and C5 play a larger role. In addition, the relative stabilization of the transition state through electrostatic interactions with the EMI cation in the acidic melt is also greater than that afforded by the weaker Lewis-acid effect provided by hydrogen bonding with water molecules in aqueous solution.

Periodic Trends and Index of Boron Lewis Acidity

Lewis acidity is customarily gauged by comparing the relative magnitude of coordinate covalent bonding energies, where the Lewis acid moiety is varied and the Lewis base is kept constant. However, the prediction of Lewis acidity from first principles is sometimes contrary to that suggested by experimental bond energies. Specifically, the order of boron trihalide Lewis acidities predicted from substituent electronegativity arguments is opposite to that inferred by experiment. Contemporary explanations for the divergence between theory, computation, and experiment have led to further consternation. Due to the fundamental importance of understanding the origin of Lewis acidity, we report periodic trends for 21 boron Lewis acids, as well as their coordinate covalent bond strengths with NH(3), utilizing ab initio, density functional theory, and natural bond orbital analysis. Coordinate covalent bond dissociation energy has been determined to be an inadequate index of Lewis acid strength. Instead, acidity is measured in the manner originally intended by Lewis, which is defined by the valence of the acid of interest. Boron Lewis acidity is found to depend upon substituent electronegativity and atomic size, differently than for known Brønsted-Lowry periodic trends. Across the second period, stronger substituent electronegativity correlates (R(2) = 0.94) with increased Lewis acidity. However, across the third period, an equal contribution from substituent electronegativity and atomic radii is correlated (R(2) = 0.98) with Lewis acidity. The data suggest that Lewis acidity depends upon electronegativity solely down group 14, while equal contribution from both substituent electronegativity and atomic size are significant down groups 16 and 17. Originally deduced from Paulings electronegativities, borons substituents determine acidity by influencing the population of its valence by withdrawing electron density. However, size effects manifest differently than previously considered, where greater sigma bond (not pi bond) orbital overlap between boron and larger substituents increase the electron density available to borons valence, thereby decreasing Lewis acidity. The computed electronegativity and size effects of substituents establish unique periodic trends that provide a novel explanation of boron Lewis acidity, consistent with first principle predictions. The findings resolve ambiguities between theory, computation, and experiment and provide a clearer understanding of Lewis acidity.

Anomeric Effect in "High Energy" Phosphate Bonds. Selective Destabilization of the Scissile Bond and Modulation of the Exothermicity of Hydrolysis

A natural bonding orbital (NBO) analysis of phosphate bonding and connection to experimental phosphotransfer potential is presented. Density functional calculations with the 6-311++G(d,p) basis set carried out on 10 model phosphoryl compounds verify that the wide variability of experimental standard free energies of hydrolysis (a phosphotransfer potential benchmark) is correlated with the instability of the scissile O-P bond through computed bond lengths. NBO analysis is used to analyze all delocalization interactions contributing to O-P bond weakening. Phosphoryl bond lengths are found to correlate strongest (R = 0.90) with the magnitude of the ground-state n(O) --> sigma*(O-P) anomeric effect. Electron-withdrawing interactions of the substituent upon the sigma(O-P) bonding orbital also correlate strongly with O-P bond lengths (R = 0.88). However, an analysis of sigma*(O-P) and sigma(O-P) populations show that the increase in sigma*(O-P) density is up to 6.5 times greater than the decrease in sigma(O-P) density. Consequently, the anomeric effect is more important than other delocalization interactions in impacting O-P bond lengths. Factors reducing anomeric power by diminishing either lone pair donor ability (solvent) or antibonding acceptor ability (substituent) are shown to result in shorter O-P bond lengths. The trends shown in this work suggest that the generalized anomeric effect provides a simple explanation for relating the sensitivity of the O-P bond to diverse environmental and substituent factors. The anomeric n(O) --> sigma*(O-P) interaction is also shown to correlate strongly with experimentally determined standard free energies of hydrolysis (R = -0.93). A causal mechanism cannot be inferred from correlation. Equally, a P-value of 1.2 x 10(-4) from an F-test indicates that it is unlikely that the ground-state anomeric effect and standard free energies of hydrolysis are coincidentally related. It is found that as the exothermicity of hydrolysis increases, the energy stabilization of the ground-state anomeric effect increases with selective destabilization of the high-energy O-P bond to be broken in hydrolysis. The anomeric effect therefore partially counteracts a larger resonance stabilization of products that makes hydrolysis exothermic and needs to be considered in achieving improved agreement between calculated and empirical energies of hydrolysis. The avenues relating the thermodynamic behavior of phosphates to underlying structural factors via the anomeric effect are discussed.

Simulation analysis of triose phosphate isomerase: conformational transition and catalysis

A theoretical approach is employed to study the catalysis of the dihydroxyacetone phosphate (DHAP) to D-glyceraldehyde 3-phosphate (GAP) reaction by the enzyme triose phosphate isomerase (TIM). The conformational change in a loop involved in protecting the active site from solvent is examined by use of X-ray data and molecular dynamics simulations. A mixed quantum-mechanics and molecular mechanics potential is used to determine the energy surface along the reaction path. The calculations address the role of the enzyme in lowering the barrier to reaction and provide a decomposition into specific residue contributions. To obtain a clearer understanding of the electronic effects, the polarization of the substrate carbonyl group by the active site residues is examined and compared with FTIR measurements on the wild-type and mutant forms of the enzyme.

Observation and interpretation of anomalous inorganic anion binding with α- and β-cyclodextrins in aqueous media

Abstract The binding constants for hexafluorophosphate, perchlorate and triflate with α- and β-cyclodextrins were quantified using calorimetry and fluorescence spectroscopy experiments in aqueous media as well as molecular orbital calculations. The association of α- and β-cyclodextrin with three commonly used counterions of large organic cations or as supporting electrolyte systems, proved to be large enough to produce significant interferences in complexation studies. In particular, the binding constant of hexafluorophosphate and β-cyclodextrin was measured to be ten times larger than the previously reported value. The enthalpies and entropies of complexation of the two receptors with the three anions under study were directly evaluated using calorimetric measurements in aqueous media. The PM3 semiempirical molecular orbital method was employed to rationalize the enhanced binding between β-cyclodexrin and hexafluorophosphate. The computed results from several energy minimizations show that inclusion comp...

Strong Coordination of Tetraphenylborate Anion to Copper(I) Bipyridine and Phenanthroline-Based Complexes and Its Effect on Catalytic Activity in the Cyclopropanation of Styrene

The synthesis, characterization, and cyclopropanation activity of tetrahedral copper(I) complexes with bipyridine- and phenanthroline-based ligands containing strongly coordinated tetraphenylborate anions are reported. Cu(I)(bpy)(BPh(4)), Cu(I)(phen)(BPh(4)), and Cu(I)(3,4,7,8-Me(4)phen)(BPh(4)) complexes are the first examples in which the BPh(4)(-) counterion chelates a transition metal center in bidentate fashion through eta(2) pi interactions with two of its phenyl rings.

Hybrid Meta-Generalized Gradient Functional Modeling of Boron-Nitrogen Coordinate Covalent Bonds.

Truhlars new generation of hybrid meta-generalized gradient functionals has been evaluated in modeling the binding enthalpies of substituted B-N coordinate covalent bonds. The short-range exchange correlation (XC) energy of coordinate covalent bonding coupled with the medium-range XC energy of noncovalent interactions results in a particularly difficult case for density functional theory (DFT). In this study, M06, M06-2X, M05, M05-2X, MPWB1K, and MPW1B95 with the 6-311++G(3df,2p) basis set have been used to evaluate four methylated ammonia trimethylboranes, (CH3)3B-N(CH3)nH3-n (n = 0 to 3), along with H3B-NH3. The predicted binding enthalpies from the new functionals have been compared to experiment as well as previous DFT (B3LYP, MPW1K) and ab initio (HF, MP2, QCISD, and QCISD(T)) results. Previously, only MP2, QCISD, and QCISD(T) were found to model the experimental energetic trend accurately. The mean absolute deviation (MAD) from experimental binding enthalpies for M06-2X and M05-2X is 0.3 and 1.6 kcal/mol, respectively. M06-2X yields a lower MAD than more expensive ab initio methods (MP2 = 1.9 kcal/mol and QCISD = 2.3 kcal/mol) and a comparable MAD to QCISD(T) (MAD = 0.4 kcal/mol). M06-2X is shown to provide a balanced account of the short- and medium-range XC energies necessary to describe the binding enthalpy of coordinate covalent bonds accurately in sterically congested molecular systems.