Kalju Kahn

Parameterization of OPLS–AA force field for the conformational analysis of macrocyclic polyketides

The parameters for the OPLS–AA potential energy function have been extended to include some functional groups that are present in macrocyclic polyketides. Existing OPLS–AA torsional parameters for alkanes, alcohols, ethers, hemiacetals, esters, and ketoamides were improved based on MP2/aug‐cc‐pVTZ and MP2/aug‐cc‐pVDZ calculations. Nonbonded parameters for the sp3 carbon and oxygen atoms were refined using Monte Carlo simulations of bulk liquids. The resulting force field predicts conformer energies and torsional barriers of alkanes, alcohols, ethers, and hemiacetals with an overall RMS deviation of 0.40 kcal/mol as compared to reference data. Densities of 19 bulk liquids are predicted with an average error of 1.1%, and heats of vaporization are reproduced within 2.4% of experimental values. The force field was used to perform conformational analysis of smaller analogs of the macrocyclic polyketide drug FK506. Structures that adopted low‐energy conformations similar to that of bound FK506 were identified. The results show that a linker of four ketide units constitutes the shortest effector domain that allows binding of the ketide drugs to FKBP proteins. It is proposed that the exact chemical makeup of the effector domain has little influence on the conformational preference of tetraketides.

Identification and Purification of Hydroxyisourate Hydrolase, a Novel Ureide-metabolizing Enzyme

We report the identification and purification of a novel enzyme from soybean root nodules that catalyzes the hydrolysis of 5-hydroxyisourate, which is the true product of the urate oxidase reaction. The product of this reaction is 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline, and the new enzyme is designated 5-hydroxyisourate hydrolase. The enzyme was purified from crude extracts of soybean root nodules ∼100-fold to apparent homogeneity with a final specific activity of 10 μmol/min/mg. The enzyme exhibited a native molecular mass of ∼68 kDa by gel filtration chromatography and migrated as a single band on SDS-polyacrylamide gel electrophoresis with a subunit molecular mass of 68 ± 2 kDa. The purified enzyme obeyed normal Michaelis-Menten kinetics, and theK m for 5-hydroxyisourate was determined to be 15 μm. The amino-terminal end of the purified protein was sequenced, and the resulting sequence was not found in any available data bases, confirming the novelty of the protein. These data suggest the existence of a hitherto unrecognized enzymatic pathway for the formation of allantoin.

Comparison of formation of reactive conformers for the SN2 displacements by CH3CO2 in water and by Asp124-CO2 in a haloalkane dehalogenase

The SN2 displacement of Cl− from 1,2-dichloroethane by acetate (CH3CO\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{_{2}^{-}}}\end{equation*}\end{document}) in water and by the carboxylate of the active site aspartate in the haloalkane dehalogenase of Xanthobacter autothropicus have been compared by using molecular dynamics simulations. In aqueous solution, six families of contact-pair structures (I–VI) were identified, and their relative concentrations and dissociation rate constants were determined. The near attack conformers (NACs) required for the SN2 displacement reaction are members of the IV (CH3COO−⋅ ⋅ ⋅CH2(Cl)CH2Cl) family and are formed in the sequence II→III→IV→NAC. The NAC subclass is defined by the —COO−⋅ ⋅ ⋅C—Cl contact distance of ≤3.41 Å and the —COO−⋅ ⋅ ⋅C—Cl angle of 157–180°. The mole percentage of NACs is 0.16%, based on the 1 M standard state. This result may be compared with 13.4 mole percentage of NACs in the Michaelis complex in the enzyme. It follows that NAC formation in the enzyme is favored by 2.6 kcal/mol. Because reaction coordinates from S to TS, both in water and in the enzyme, pass via NAC (i.e., S → NAC → TS), the reduction in the S → NAC barrier by 2.6 kcal/mol accounts for ≈25% of the reduction of total barrier in the S → TS (10.7 kcal/mol). The remaining 75% of the advantage of the enzymatic reaction revolves around the efficiency of NAC → TS step. This process, based on previous studies, is discussed briefly.

Anharmonic vibrational analysis of water with traditional and explicitly correlated coupled cluster methods.

It is well known that the convergence of harmonic frequencies with respect to the basis set size in traditional correlated calculations is slow. We now report that the convergence of cubic and quartic force constants in traditional CCSD(T) calculations on H(2)O with Dunnings cc-pVXZ family of basis sets is also frustratingly slow. As an alternative, we explore the performance of R12-based explicitly correlated methods at the CCSD(T) level. Excellent convergence of harmonic frequencies and cubic force constants is provided by these explicitly correlated methods with R12-suited basis irrespective of the used standard approximation and/or the correlation factor. The Slater type geminal, however, outperforms the linear r(12) for quartic force constants and vibrational anharmonicity constants. The converged force constants from explicitly correlated CCSD(T) calculations succeed in reproducing the fundamental frequencies of water molecule with spectroscopic accuracy after corrections for post-CCSD(T) effects are made.

Convergence of third order correlation energy in atoms and molecules

We have investigated the convergence of third order correlation energy within the hierarchies of correlation consistent basis sets for helium, neon, and water, and for three stationary points of hydrogen peroxide. This analysis confirms that singlet pair energies converge much slower than triplet pair energies. In addition, singlet pair energies with (aug)‐cc‐pVDZ and (aug)‐cc‐pVTZ basis sets do not follow a converging trend and energies with three basis sets larger than aug‐cc‐pVTZ are generally required for reliable extrapolations of third order correlation energies, making so the explicitly correlated R12 calculations preferable.

α-Ketoamides and α-Ketocarbonyls: Conformational analysis and development of all-atom OPLS force field

Abstract The molecular structures and barriers for the internal rotation around the OC CO single bond in four α-ketoamides and eight α-ketocarbonyls have been determined from the MP3/aug-cc-pVDZ and MP2/aug-cc-pVDZ calculations. α-Ketocarbonyls with non-bulky substituents adopt planar conformations with two carbonyl oxygens in s- trans arrangement. The s- cis conformation is significantly less stable due to the electrostatic repulsion between the two carbonyl groups. Primary and secondary α-ketoamides are planar when the substituent at the carbonyl carbon is hydrogen or methyl group but tertiary α-ketoamides adopt a conformation where the OC CO unit is significantly bent. Based on current ab initio structural data, a set of OPLS AA force field parameters has been derived. These parameters can be used for the modeling of a variety of α-ketoamide or α-ketocarbonyl containing drugs such as novel protease inhibitors or neuroregenerative polyketides.

Improved efficiency of focal point conformational analysis with truncated correlation consistent basis sets.

It has been suggested that the computational cost of correlated ab initio calculations could be reduced efficiently by using truncated basis sets on hydrogen atoms (Mintz et al., J Chem Phys 2004, 121, 5629). We now explore this proposal in the context of conformational analysis of small molecules, such as hydrogen peroxide, dimethyl ether, ethyl methyl ether, formic acid, methyl formate, and several small alcohols. It is found that truncated correlation consistent basis sets that lack certain higher angular momentum functions on hydrogen atoms offer accuracy similar to traditional Dunnings basis sets for conformational analysis. Combination of such basis sets with the basis set extrapolation technique to estimate Hartree–Fock and Møller–Plesset second order energies provides composite extrapolation model chemistries that are significantly more accurate and faster than analogous single point calculations with traditional correlation consistent basis sets. Root mean square errors of best composite extrapolation model chemistries on the used set of molecules are within 0.03 kcal/mol of traditional focal point conformational energies. The applicability of composite extrapolation methods is illustrated by performing conformational analysis of tert‐butanol and cyclohexanol. For comparison, conformational energies calculated with popular molecular mechanics force fields are also given.

Principles of Biomolecular Recognition

Biomolecular recognition, the process by which biomolecules recognize and bind to their molecular targets, typically highly specific, high affinity and reversible, and is generalizable to an effectively unlimited range of aqueous analytes. Consequently, it has been exploited in a wide range of diagnostic and synthetic technologies. Biomolecular recognition is typically driven by many weak interactions working in concert. The most important of these interactions include (i) the electrostatic interaction due to permanent charges, dipoles, and quadrupoles, (ii) the polarization of charge distributions by the interaction partner leading to induction and dispersion forces, (iii) Pauli-exclusion principle-derived inter-atomic repulsion, and (iv) a strong, “attractive” force arising largely from the entropy of the solvent and termed the hydrophobic effect. Because the aqueous environment significantly reduces the impact of electrostatic and induction interactions, the hydrophobic effect is often the dominant force stabilizing the formation of correct biomolecule–target complexes. The other effects are nevertheless important in defining the specificity of the macromolecule toward its target by destabilizing binding events in which a less-than-ideal network of interactions between two partners would be established.

Communication: Convergence of anharmonic infrared intensities of hydrogen fluoride in traditional and explicitly correlated coupled cluster calculations

It is shown that the convergence of anharmonic infrared spectral intensities with respect to the basis set size is much enhanced in explicitly correlated calculations as compared to traditional configuration interaction type wave function expansion. Explicitly correlated coupled cluster (CC) calculations using Slater-type geminal correlation factor (CC-F12) yield well-converged dipole derivatives and vibrational intensities for hydrogen fluoride with basis set involving f functions on the heavy atom. Combination of CC-F12 with singles, doubles, and non-iterative triples (CCSD(T)-F12) with small corrections due to quadruple excitations, core-electron correlation, and relativistic effects yields vibrational line positions, dipole moments, and transition dipole matrix elements in good agreement with the best experimental values.

Anharmonic vibrational analysis of water at CCSD(T) level: Comparison of traditional and explicitly correlated methods

Achieving the spectroscopic accuracy in ab initio calculation of harmonic vibrational frequencies and vibrational anharmonicities is challenging due to two well-understood limitations. First, accurate results require a good description of electron correlation. Second, correlated calculations require large one-electron basis sets. It is well known that the convergence of harmonic frequencies with respect to the basis set size is slow. We now report that the convergence of cubic and quartic force constants in traditional CCSD(T) calculations of H2O with Dunnings cc-pVXZ family of basis sets is also frustratingly slow. As an alternative, we explore the performance of R12/B, R12/C and F12/C explicitly correlated methods at the CCSD(T) level. We find that an excellent convergence of harmonic frequencies and cubic force constants is provided by all three explicitly correlated methods with modest R12 basis sets; larger R12 basis sets appear necessary for the accurate description of quartic force constants and v...