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.

Human immunodeficiency virus 1 integrase (HIV-1 IN) is the enzyme responsible for integrating the viral DNA into the host genome, and is essential to the replication of the virus. L-Chicoric acid (L-CA) is a bidentate catechol that has been identified as a potent inhibitor of HIV-1 IN. Using the new Autodock 4.0 free-energy function we have obtained a L-CA binding mode that explains its observed potency and is consistent with available experimental data. Because of the alpha,beta-unsaturated ester functionality of the side arms of L-CA we first performed an extensive conformational analysis of L-CA using semiempirical and ab initio calculations. As a result we have identified two distinct L-CA binding modes, one for the s-cis/s-cis and another for the s-cis/s-trans isomers. The most stable conformer was found to be the structure with the alpha,beta-unsaturated ester in the s-cis conformation for both arms of L-CA. This conformer also gave the top-ranked docking solution. Analysis of the interactions with key IN residues, combined with results using a L-CA tetraacetylated derivative and a Q148A IN mutant, correlate well with the experimental data.

A docking study of L-chicoric acid with HIV-1 integrase.

MNDO has been parametrized for bromine. Since d atomic orbitals (AOS) are not included, the calculations are restricted to BrI. Heats of formation, molecular geometries, ionization energies, and dioole moments are reproduced with useful accuracy.

Ground States of Molecules. 67.* MNDO Calculations for Compounds Containing Iodine

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 magnitudes of secondary deuterium isotope effects (SDIE) are generally in the range of 0.9 < k/sub H//k/sub D/ < 1.25, and are often satisfactorily rationalized by the zero-point energy (ZPE) change on going from reactant to transition state due to C-H rehybridization. They now report a far larger SDIE for the title reaction. Its rationalization on the basis of transition state theory suggests that it more closely resembles a primary isotope effect.

An unusually large secondary deuterium isotope effect. Thermal trans-cis isomerization of trans-1-phenylcyclohexene

Calculations have been carried out at the MP4SDO//6-31G* level for corner-protonated cyclopropane that show it to have an unsymmetrical π complex structure, the formal charges on the basal atoms being in the ratio 3:2; implications concerning the norbornyl cation are discussed.

Eamonn F. Healy

Papers

A docking study of L-chicoric acid with HIV-1 integrase.

Ground States of Molecules. 67.* MNDO Calculations for Compounds Containing Iodine

Mechanism of the 1,5-sigmatropic hydrogen shift in 1,3-pentadiene

An unusually large secondary deuterium isotope effect. Thermal trans-cis isomerization of trans-1-phenylcyclohexene

A high level ab initio study of corner-protonated cyclopropane