A new method for obtaining optimized parameters for semiempirical methods has been developed and applied to the modified neglect of diatomic overlap (MNDO) method. The method uses derivatives of calculated values for properties with respect to adjustable parameters to obtain the optimized values of parameters. The large increase in speed is a result of using a simple series expression for calculated values of properties rather than employing full semiempirical calculations. With this optimization procedure, the rate-determining step for parameterizing elements changes from the mechanics of parameterization to the assembling of experimental reference data.

Optimization of parameters for semiempirical methods I. Method

Scaling factors for obtaining fundamental vibrational frequencies, low-frequency vibrations, zero-point vibrational energies (ZPVE), and thermal contributions to enthalpy and entropy from harmonic frequencies determined at 19 levels of theory have been derived through a least-squares approach. Semiempirical methods (AM1 and PM3), conventional uncorrelated and correlated ab initio molecular orbital procedures [Hartree−Fock (HF), Moller−Plesset (MP2), and quadratic configuration interaction including single and double substitutions (QCISD)], and several variants of density functional theory (DFT:  B-LYP, B-P86, B3-LYP, B3-P86, and B3-PW91) have been examined in conjunction with the 3-21G, 6-31G(d), 6-31+G(d), 6-31G(d,p), 6-311G(d,p), and 6-311G(df,p) basis sets. The scaling factors for the theoretical harmonic vibrational frequencies were determined by a comparison with the corresponding experimental fundamentals utilizing a total of 1066 individual vibrations. Scaling factors suitable for low-frequency vib...

Harmonic Vibrational Frequencies: An Evaluation of Hartree−Fock, Møller−Plesset, Quadratic Configuration Interaction, Density Functional Theory, and Semiempirical Scale Factors

A significant modification to the additive all-atom CHARMM lipid force field (FF) is developed and applied to phospholipid bilayers with both choline and ethanolamine containing head groups and with both saturated and unsaturated aliphatic chains. Motivated by the current CHARMM lipid FF (C27 and C27r) systematically yielding values of the surface area per lipid that are smaller than experimental estimates and gel-like structures of bilayers well above the gel transition temperature, selected torsional, Lennard-Jones and partial atomic charge parameters were modified by targeting both quantum mechanical (QM) and experimental data. QM calculations ranging from high-level ab initio calculations on small molecules to semiempirical QM studies on a 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) bilayer in combination with experimental thermodynamic data were used as target data for parameter optimization. These changes were tested with simulations of pure bilayers at high hydration of the following six lipids: ...

Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types

MNDO/AM1‐type parameters for twelve elements have been optimized using a newly developed method for optimizing parameters for semiempirical methods. With the new method, MNDO‐PM3, the average difference between the predicted heats of formation and experimental values for 657 compounds is 7.8 kcal/mol, and for 106 hypervalent compounds, 13.6 kcal/mol. For MNDO the equivalent differences are 13.9 and 75.8 kcal/mol, while those for AM1, in which MNDO parameters are used for aluminum, phosphorus, and sulfur, are 12.7 and 83.1 kcal/mol, respectively. Average errors for ionization potentials, bond angles, and dipole moments are intermediate between those for MNDO and AM1, while errors in bond lengths are slightly reduced.

Optimization of parameters for semiempirical methods II. Applications

Several modifications that have been made to the NDDO core-core interaction term and to the method of parameter optimization are described. These changes have resulted in a more complete parameter optimization, called PM6, which has, in turn, allowed 70 elements to be parameterized. The average unsigned error (AUE) between calculated and reference heats of formation for 4,492 species was 8.0 kcal mol−1. For the subset of 1,373 compounds involving only the elements H, C, N, O, F, P, S, Cl, and Br, the PM6 AUE was 4.4 kcal mol−1. The equivalent AUE for other methods were: RM1: 5.0, B3LYP 6–31G*: 5.2, PM5: 5.7, PM3: 6.3, HF 6–31G*: 7.4, and AM1: 10.0 kcal mol−1. Several long-standing faults in AM1 and PM3 have been corrected and significant improvements have been made in the prediction of geometries.

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Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements.

The assumption, common at the undergraduate level, that hydrogen with its single electron can form only one covalent bond is belied by the many structures that have been characterized with hydrogens bonded to two atoms. The 3-center bond responsible for such bridging hydrogens is facilitated by the spherical distribution inherent to the 1s electron. Here we demonstrate how topological analysis of the electron density of molecules with bridging hydrogens can inform a deeper appreciation of the character and complexity of the chemical bond. DFT calculations are performed to generate the electron density for the experimental structures of a range of complexes with bridging hydrogens. Analysis using both the Atoms in Molecules (AIM) perspective and a range of electron indicators and localization functions demonstrates the utility of topological analysis for the detection and characterization of multi-center bonding. 

Topological Analysis of the Electron Density of Molecules with Bridging Hydrogens To Tackle the Chemical Structure Monolith

Protein dynamics of [Cu-Zn] superoxide dismutase (SOD1): How protein motions at the global and local levels impact the reactivity of SOD1.

the present work we show that the mixed micelle system is ideally suited for inhibition studies with phospholipase A2 since both the inhibitor and substrate can compete for the binding to the active site of the enzyme in the surface of the mixed micelle and is free from the complexities that arise from lipid-lipid interactions. Although the mixed-micelle system is perhaps a poor model of a biological membrane, it provides a reliable method for ranking inhibitors according to their relative free energies of interaction with the enzyme. Mixed micelles for inhibition studies were prepared by soni- cating fixed amounts of Triton X-100 (40 mM) and substrate (dipalmitoyl phosphatidylcholine, 5 mM) with variable amounts of inhibitor in water-containing CaC12 (10 mM).I2 Enzyme was added, and the reaction velocity was determined in a pH-stat at pH 8.0 and 40 T9 The initial enzymatic velocity as a function of the concentration of inhibitor

Mechanism of the 1,5-Sigmatropic Hydrogen Shift in 1,3-Pentadiene

The aluminum hydride reduction of 3.4-cpoxycyclopentene to 3cyclopentenol has been previously observed' and the complete regiospekfkity of the reaction is confvmed h-. A mechanism is proposed involving initial complexation of the aMminum hydride anion with the Qbuble bond followed by hydride transfer to the 3-Carbon. Analysis of the atomic charges detumined fmm semiempirical electmstaic potentials support the proposed mechanism. Spectroscopic analysis of the resultant alcohol indicates the presence of an OH--rr intramolecular hydrogen bonded interaction. The epoxidation of cyclopeutadiene with peracetic acid yields epoxide 1. Reduction of 1 with Lithium Aluminum Hydride iu ether yields only 3-cyclopentcnol. 2, in 65% yield. Use of a threefold excess of LAH ineased this yield to 85%.

Eamonn F. Healy

Papers

Topological Analysis of the Electron Density of Molecules with Bridging Hydrogens To Tackle the Chemical Structure Monolith

Protein dynamics of [Cu-Zn] superoxide dismutase (SOD1): How protein motions at the global and local levels impact the reactivity of SOD1.

Mechanism of the 1,5-Sigmatropic Hydrogen Shift in 1,3-Pentadiene

A Study of the Aluminum Hydride Reduction of Unsaturated Cyclic Epoxides.

Bonding in clusters. part 3. protonation of nido-pentaborane(9), nido-hexaborane(10), and closo-hexaborane(6)(2-)