The block-localized wavefunction (BLW) approach is an ab initio valence bond (VB) method incorporating the efficiency of molecular orbital (MO) theory. It can generate the wavefunction for a resonance structure or diabatic state self-consistently by partitioning the overall electrons and primitive orbitals into several subgroups and expanding each block-localized molecular orbital in only one subspace. Although block-localized molecular orbitals in the same subspace are constrained to be orthogonal (a feature of MO theory), orbitals between different subspaces are generally nonorthogonal (a feature of VB theory). The BLW method is particularly useful in the quantification of the electron delocalization (resonance) effect within a molecule and the charge-transfer effect between molecules. In this paper, we extend the BLW method to the density functional theory (DFT) level and implement the BLW-DFT method to the quantum mechanical software GAMESS. Test applications to the pi conjugation in the planar allyl radical and ions with the basis sets of 6-31G(d), 6-31+G(d), 6-311+G(d,p), and cc-pVTZ show that the basis set dependency is insignificant. In addition, the BLW-DFT method can also be used to elucidate the nature of intermolecular interactions. Examples of pi-cation interactions and solute-solvent interactions will be presented and discussed. By expressing each diabatic state with one BLW, the BLW method can be further used to study chemical reactions and electron-transfer processes whose potential energy surfaces are typically described by two or more diabatic states.

Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV.

Molecular dynamics (MD) simulations have been performed at the atomic level to study the ammonium/ammonia transport across the Escherichia coli AmtB membrane protein. Although ammonia primarily exists in the form of NH(4)(+) in aqueous solution, the recent X-ray structure determination of AmtB reveals that the ammonium/ammonia transporter proteins are ammonia-conducting channels rather than ammonium ion transporters [Khademi, S.; et al. Science 2004, 305, 1587; Zheng, L.; et al. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 17090]. Our simulations showed that the entrance of NH(4)(+) into the periplasmic recruitment vestibule requires only 3.1 kcal/mol of energy. This is consistent with the X-ray crystal structure, where one NH(4)(+) is captured in the binding vestibule. In this vestibule, NH(4)(+) loses one water of hydration, but the loss is compensated by a hydrogen bond, first with the backbone carbonyl oxygen of Phe161 then with the hydroxyl group of Ser219, as well as the stabilizing pi-cation interactions with the aromatic rings of Trp148 and Phe107 in the AmtB protein. In the end of this recruitment vestibule, the phenyl ring of Phe107 dynamically switches to an open state. This is correlated with a slight rotation and shifting of the indole ring of Trp148, which eventually creates a slot for the initially buried carboxylate group of Asp160 to become exposed to the bulk solvent. A hydrogen bond wire between NH(4)(+) and the carboxylate group of Asp160 via two water molecules was observed. Thus, Asp160 is most likely the proton acceptor from NH(4)(+). This explains the high conservation of Asp160 in Amt proteins and why the D160A mutant would completely quench the activity of AmtB [Javelle, A.; et al. J. Biol. Chem. 2004, 279, 8530; Marini, A. M.; et al. Curr. Genet. 2006, 49, 364]. Once NH(4)(+) deprotonates, the phenyl ring of Phe215 rotates to open, and the subsequent passage of NH(3) through the channel is straightforward.

In this paper, a new solvation model is proposed for simulations of biomolecules in aqueous solutions that combines the strengths of explicit and implicit solvent representations. Solute molecules are placed in a spherical cavity filled with explicit water, thus providing microscopic detail where it is most needed. Solvent outside of the cavity is modeled as a dielectric continuum whose effect on the solute is treated through the reaction field corrections. With this explicit/implicit model, the electrostatic potential represents a solute molecule in an infinite bath of solvent, thus avoiding unphysical interactions between periodic images of the solute commonly used in the lattice-sum explicit solvent simulations. For improved computational efficiency, our model employs an accurate and efficient multiple-image charge method to compute reaction fields together with the fast multipole method for the direct Coulomb interactions. To minimize the surface effects, periodic boundary conditions are employed for nonelectrostatic interactions. The proposed model is applied to study liquid water. The effect of model parameters, which include the size of the cavity, the number of image charges used to compute reaction field, and the thickness of the buffer layer, is investigated in comparison with the particle-mesh Ewald simulations as a reference. An optimal set of parameters is obtained that allows for a faithful representation of many structural, dielectric, and dynamic properties of the simulated water, while maintaining manageable computational cost. With controlled and adjustable accuracy of the multiple-image charge representation of the reaction field, it is concluded that the employed model achieves convergence with only one image charge in the case of pure water. Future applications to pKa calculations, conformational sampling of solvated biomolecules and electrolyte solutions are briefly discussed.

Decoy receptor 3 (DCR3) halts both Fas ligand– and LIGHT-induced cell deaths, which are required for pancreatic β cell damage in autoimmune diabetes. To directly investigate the therapeutic potential of DCR3 in preventing this disease, we generated transgenic nonobese diabetic mice, which overexpressed DCR3 in β cells. Transgenic DCR3 protected mice from autoimmune and cyclophosphamide-induced diabetes in a dose-dependent manner and significantly reduced the severity of insulitis. Local expression of the transgene did not alter the diabetogenic properties of systemic lymphocytes or the development of T helper 1 or T regulatory cells. The transgenic islets had a higher transplantation success rate and survived for longer than wild-type islets. We have demonstrated for the first time that the immune-evasion function of DCR3 inhibits autoimmunity and that genetic manipulation of grafts may improve the success and survival of islet transplants.

Combined QM(PM3)/MM molecular dynamics simulations together with QM(DFT)/MM optimizations for key configurations have been performed to elucidate the enzymatic catalysis mechanism on the detoxification of paraoxon by phosphotriesterase (PTE). In the simulations, the PM3 parameters for the phosphorous atom were re-optimized. The equilibrated configuration of the enzyme/substrate complex showed that paraoxon can strongly bind to the more solventexposed metal ion Zn β , but the free energy profile along the binding path demonstrated that the binding is thermodynamically unfavorable. This explains why the crystal structures of PTE with substrate analogues often exhibit long distances between the phosphoral oxygen and Zn β . The subsequent S N 2 reaction plays the key role in the whole process, but controversies exists over the identity of the nucleophilic species which could be either a hydroxide ion terminally coordinated to Zn α or the μ-hydroxo bridge between the α-and β-metals. Our simulations supported the latter and showed that the rate-limiting step is the distortion of the bound paraoxon in order to approach the bridging hydroxide. After this preparation step, the bridging hydroxide ion attacks the phosphorous center and replaces the diethyl phosphate with a low barrier. Thus, a plausible way to engineer PTE with enhanced catalytic activity is to stabilize the deformed paraoxon. Conformational analyses indicate that Trp131 is the closest residue to the phosphoryl oxygen, and mutations to Arg or Gln or even Lys which can shorten the hydrogen bond distance with the phosphoryl oxygen could potentially lead to a mutant with enhanced activity for the detoxification of organophosphates.

Background: Bioinformatics tools for automatic processing of biomedical literature are invaluable for both the design and interpretation of large-scale experiments. Many information extraction (IE) systems that incorporate natural language processing (NLP) techniques have thus been developed for use in the biomedical field. A key IE task in this field is the extraction of biomedical relations, such as protein-protein and gene-disease interactions. However, most biomedical relation extraction systems usually ignore adverbial and prepositional phrases and words identifying location, manner, timing, and condition, which are essential for describing biomedical relations. Semantic role labeling (SRL) is a natural language processing technique that identifies the semantic roles of these words or phrases in sentences and expresses them as predicate-argument structures. We construct a biomedical SRL system called BIOSMILE that uses a maximum entropy (ME) machine-learning model to extract biomedical relations. BIOSMILE is trained on BioProp, our semi-automatic, annotated biomedical proposition bank. Currently, we are focusing on 30 biomedical verbs that are frequently used or considered important for describing molecular events.

Rotation barriers in the group IVB ethane congeners H(3)X-YH(3) (X, Y = C, Si, Ge, Sn, Pb) have been systematically studied and deciphered using the ab initio valence bond theory in terms of the steric strain and hyperconjugation effect. Our results show that in all cases the rotation barriers are dominated by the steric repulsion whereas the hyperconjugative interaction between the X-H bond orbitals and the vicinal Y-H antibond orbitals (and vice versa) plays a secondary role, although indeed the hyperconjugation effect favors staggered structures. By the independent estimations of the hyperconjugative and steric interactions in the process of rotations, we found that the structural effect which mainly refers to the central X-Y bond relaxation makes a small contribution to the rotational barriers. Therefore, we conclude that both the rigid and fully relaxed rotations in the group IVB ethane congeners H(3)X-YH(3) observe the same mechanism which is governed by the conventional steric repulsion.