Consistent treatment of inter- and intramolecular polarization in molecular mechanics calculations

A protocol is described for the treatment of molecular polarization in force field calculations. The resulting model is consistent in that both inter- and intramolecular polarization are handled within a single scheme. An analytical formula for removing intramolecular polarization from a set of atomic multipoles for an arbitrary static structure or conformation is given. With the help of the intramolecular polarization, these permanent atomic multipoles can then be applied in modeling alternative conformations of a molecule. Equipped with this simple technique, one can derive transferable electrostatic parameters for peptides and proteins using flexible model compounds such as dipeptides. The proposed procedure is tested for its ability to describe the electrostatic potential around various configurations of the N-methylacetamide dimer. The effect of different intramolecular polarization schemes on the accuracy of a force field model of the electrostatic potential of alanine dipeptide is investigated. A group-based scheme for including direct intramolecular polarization is shown to be most successful in accounting for the conformational dependence of electrostatic potentials.     

A valence bond model for aqueous Cu(II) and Zn(II) ions in the AMOEBA polarizable force field

A general molecular mechanics (MM) model for treating aqueous Cu²⁺ and Zn²⁺ ions was developed based on valence bond (VB) theory and incorporated into the atomic multipole optimized energetics for biomolecular applications (AMOEBA) polarizable force field. Parameters were obtained by fitting MM energies to that computed by ab initio methods for gas‐phase tetra‐ and hexa‐aqua metal complexes. Molecular dynamics (MD) simulations using the proposed AMOEBA‐VB model were performed for each transition metal ion in aqueous solution, and solvent coordination was evaluated. Results show that the AMOEBA‐VB model generates the correct square‐planar geometry for gas‐phase tetra‐aqua Cu²⁺ complex and improves the accuracy of MM model energetics for a number of ligation geometries when compared to quantum mechanical (QM) computations. On the other hand, both AMOEBA and AMOEBA‐VB generate results for Zn²⁺–water complexes in good agreement with QM calculations. Analyses of the MD trajectories revealed a six‐coordination first solvation shell for both Cu²⁺ and Zn²⁺ ions in aqueous solution, with ligation geometries falling in the range reported by previous studies. © 2012 Wiley Periodicals, Inc.     

Development of small molecule inhibitors and probes of human SUMO deconjugating proteases

Sentrin specific proteases (SENPs) are responsible for activating and deconjugating SUMO (Small Ubiquitin like MOdifier) from target proteins. It remains difficult to study this posttranslational modification due to the lack of reagents that can be used to block the removal of SUMO from substrates. Here, we describe the identification of small molecule SENP inhibitors and active site probes containing aza-epoxide and acyloxymethyl ketone (AOMK) reactive groups. Both classes of compounds are effective inhibitors of hSENPs 1, 2, 5, and 7 while only the AOMKs efficiently inhibit hSENP6. Unlike previous reported peptide vinyl sulfones, these compounds covalently labeled the active site cysteine of multiple recombinantly expressed SENP proteases and the AOMK probe showed selective labeling of these SENPs when added to complex protein mixtures. The AOMK compound therefore represents promising new reagents to study the process of SUMO deconjugation.     

Stereochemistry of the hygrolidins

The stereochemistry shown in 6 has been determined by computer modelling for hygrolidin, prototypical member of a new class of macrolide antibiotics.     

Protein structure prediction using a combination of sequence homology and global energy minimization: II. Energy functions

A protein energy surface is constructed. Validation is through applications of global energy minimization to surface loops of protein crystal structures. For 9 of 10 predictions, the native backbone conformation is identified correctly. Electrostatic energy is modeled as a pairwise sum of interactions between anisotropic atomic charge densities. Model repulsion energy has a softness similar to that seen in ab initio data. Intrinsic torsional energy is modeled as a sum over pairs of adjacent torsion angles of 2-dimensional Fourier series. Hydrophobic energy is that of a hydration shell model. The remainder of hydration free energy is obtained as the energetic effect of a continuous dielectric medium. Parameters are adjusted to reproduce the following data: a complete set of ab initio energy surfaces, meaning one for each pair of adjacent torsion angles of each blocked amino acid; experimental crystal structures and sublimation energies for nine model compounds; ab initio energies over 1014 conformations of 15 small-molecule dimers; and experimental hydration free energies for 48 model compounds. All ab initio data is at the Hartree–Fock/6–31G* level. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 548–573, 1998     

Investigations of substituted benzofuran-3-carboxylates,benzo[1,2-b:4,5-b']difurans and benzo[1,2-b:4,3-b']difurans

The Michael addition of ethyl acetoacetate to benzoquinone, toluquinone, and chlorobenzo-quinone leads to formation of substituted 5-hydroxybenzofuran-3-earboxylates and linear benzo-[1,2-b:4,5-b']difurans. The previously reported structural proof for the benzodifurans obtained from chlorobenzoquinone and toluquinone, although correct in the conclusion, is shown to be invalid. Proof of the linear benzodifuran structures was obtained by comparison of the uv spectra with authentic angular benzo[1,2-b:4,3-b']difurans.     

Simple Zeros of the Riemann Zeta-Function

Assuming the Riemann Hypothesis, Montgomery showed by meansof his pair correlation method that at least two-thirds of thezeros of Riemann's zeta-function are simple. Later he and Taylorimproved this to 67.25 percent and, more recently, Cheer andGoldston increased the percentage to 67.2753. Here we proveby a new method that if the Riemann and Generalized LindelöofHypotheses hold, then at least 70.3704 percent of the zerosare simple and at least 84.5679 percent are distinct. Our methoduses mean value estimates for various functions defined by Dirichletseries sampled at the zeros of the Riemann zeta-function. 1991Mathematics Subject Classification: 11M26.