An effective molecular blocker of ion channel of M2 protein as anti-influenza a drug.

Design of a drug compound that can effectively bind to the M2 ion channel and block the diffusion of hydrogen ions (H) through and inhibit influenza A virus replication is an important task. Known anti-influenza drugs amantadine and rimantadine have a weak effect on influenza A virus. A new class of positively charged, +2 e.

Role of Ionizing Amino Acid Residues in the Process of DNA Binding by Human AP Endonuclease 1 and in Its Catalysis.

In the repair of the damage to bases, human apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is a key participant via the DNA base excision repair pathway. APE1 cleaves AP sites in DNA, which are potentially cytotoxic and highly mutagenic if left unrepaired. According to existing structural data, this enzyme's active site contains many polar amino acid residues, which form extensive contacts with a DNA substrate.

The Role of Active-Site Residues Phe98, His239, and Arg243 in DNA Binding and in the Catalysis of Human Uracil-DNA Glycosylase SMUG1.

Human SMUG1 (hSMUG1) hydrolyzes the -glycosidic bond of uracil and some uracil lesions formed in the course of epigenetic regulation. Despite the functional importance of hSMUG1 in the DNA repair pathway, the damage recognition mechanism has been elusive to date. In the present study, our objective was to build a model structure of the enzyme-DNA complex of wild-type hSMUG1 and several hSMUG1 mutants containing substitution F98W, H239A, or R243A.

Roles of Active-Site Amino Acid Residues in Specific Recognition of DNA Lesions by Human 8-Oxoguanine-DNA Glycosylase (OGG1).

Human 8-oxoguanine-DNA glycosylase (hOGG1) possesses very high specificity for 8-oxoguanine (oxoG), even though this damaged base differs from normal guanine by only two atoms. Our aim was to determine the roles of certain catalytically important amino acid residues in the hOGG1 enzymatic pathway and describe their involvement in the mechanism of DNA lesion recognition. Molecular dynamic simulation and pre-steady-state fluorescence kinetics were performed to analyze the conformational behavior of wild-type hOGG1 and mutants G42S, D268A, and K249Q, as well as damaged and undamaged DNA.

A comprehensive analysis of the computed tautomer fractions of the imidazole ring of histidines in Loligo vulgaris.

A recently introduced electrostatic-based method to determine the pKa values of ionizable residues and fractions of ionized and tautomeric forms of histidine (His) and acid residues in proteins, at a given fixed pH, is applied here to the analysis of a His-rich protein, namely Loligo vulgaris (pdb id 1E1A), a 314-residue all-β protein. The average tautomeric fractions for the imidazole ring of each of the six histidines in the sequence were computed using an approach that includes, but is not limited to, molecular dynamic simulations coupled with calculations of the ionization states for all 94 ionizable residues of protein 1E1A in water at pH 6.5 and 300 K.

Coupled molecular dynamics and continuum electrostatic method to compute the ionization pKa's of proteins as a function of pH. Test on a large set of proteins.

A computational method, to predict the pKa values of the ionizable residues Asp, Glu, His, Tyr, and Lys of proteins, is presented here. Calculation of the electrostatic free-energy of the proteins is based on an efficient version of a continuum dielectric electrostatic model. The conformational flexibility of the protein is taken into account by carrying out molecular dynamics simulations of 10 ns in implicit water.

Evaluation of the Gibbs Free Energy Changes and Melting Temperatures of DNA/DNA Duplexes Using Hybridization Enthalpy Calculated by Molecular Dynamics Simulation.

A molecular dynamics simulation approach was applied for the prediction of the thermal stability of oligonucleotide duplexes. It was shown that the enthalpy of the DNA/DNA complex formation could be calculated using this approach. We have studied the influence of various simulation parameters on the secondary structure and the hybridization enthalpy value of Dickerson-Drew dodecamer.

MDTRA: a molecular dynamics trajectory analyzer with a graphical user interface.

Most of existing software for analysis of molecular dynamics (MD) simulation results is based on command-line, script-guided processes that require the researchers to have an idea about programming language constructions used, often applied to the one and only product. Here, we describe an open-source cross-platform program, MD Trajectory Reader and Analyzer (MDTRA), that performs a large number of MD analysis tasks assisted with a graphical user interface. The program has been developed to facilitate the process of search and visualization of results.

Potential of mean force of water-proton bath and molecular dynamic simulation of proteins at constant pH.

An advanced implicit solvent model of water-proton bath for protein simulations at constant pH is presented. The implicit water-proton bath model approximates the potential of mean force of a protein in water solvent in a presence of hydrogen ions. Accurate and fast computational implementation of the implicit water-proton bath model is developed using the continuum electrostatic Poisson equation model for calculation of ionization equilibrium and the corrected MSR6 generalized Born model for calculation of the electrostatic atom-atom interactions and forces.

Conformational dynamics of abasic DNA upon interactions with AP endonuclease 1 revealed by stopped-flow fluorescence analysis.

Apurinic/apyrimidinic (AP) sites are abundant DNA lesions arising from exposure to UV light, ionizing radiation, alkylating agents, and oxygen radicals. In human cells, AP endonuclease 1 (APE1) recognizes this mutagenic lesion and initiates its repair via a specific incision of the phosphodiester backbone 5' to the AP site. We have investigated a detailed mechanism of APE1 functioning using fluorescently labeled DNA substrates.

Advances in implicit models of water solvent to compute conformational free energy and molecular dynamics of proteins at constant pH.

Modern implicit solvent models for macromolecular simulations in water-proton bath are considered. The fundamental quantity that implicit models approximate is the solute potential of mean force, which is obtained by averaging over solvent degrees of freedom. The implicit solvent models suggest practical ways to calculate free energies of macromolecular conformations taking into account equilibrium interactions with water solvent and proton bath, while the explicit solvent approach is unable to do that due to the need to account for a large number of solvent degrees of freedom.

Blind docking method combining search of low-resolution binding sites with ligand pose refinement by molecular dynamics-based global optimization.

This study describes the development of a new blind hierarchical docking method, bhDock, its implementation, and accuracy assessment. The bhDock method uses two-step algorithm. First, a comprehensive set of low-resolution binding sites is determined by analyzing entire protein surface and ranked by a simple score function.

Identifying native-like protein structures with scoring functions based on all-atom ECEPP force fields, implicit solvent models and structure relaxation.

Availability of energy functions which can discriminate native-like from non-native protein conformations is crucial for theoretical protein structure prediction and refinement of low-resolution protein models. This article reports the results of benchmark tests for scoring functions based on two all-atom ECEPP force fields, that is, ECEPP/3 and ECEPP05, and two implicit solvent models for a large set of protein decoys. The following three scoring functions are considered: (i) ECEPP05 plus a solvent-accessible surface area model with the parameters optimized with a set of protein decoys (ECEPP05/SA); (ii) ECEPP/3 plus the solvent-accessible surface area model of Ooi et al.

FAMBE-pH: a fast and accurate method to compute the total solvation free energies of proteins.

A fast and accurate method to compute the total solvation free energies of proteins as a function of pH is presented. The method makes use of a combination of approaches, some of which have already appeared in the literature; (i) the Poisson equation is solved with an optimized fast adaptive multigrid boundary element (FAMBE) method; (ii) the electrostatic free energies of the ionizable sites are calculated for their neutral and charged states by using a detailed model of atomic charges; (iii) a set of optimal atomic radii is used to define a precise dielectric surface interface; (iv) a multilevel adaptive tessellation of this dielectric surface interface is achieved by using multisized boundary elements; and (v) 1:1 salt effects are included. The equilibrium proton binding/release is calculated with the Tanford-Schellman integral if the proteins contain more than approximately 20-25 ionizable groups; for a smaller number of ionizable groups, the ionization partition function is calculated directly.

Coupling between conformation and proton binding in proteins.

Interest centers here on whether the use of a fixed charge distribution of a protein solute, or a treatment that considers proton-binding equilibria by solving the Poisson equation, is a better approach to discriminate native from non-native conformations of proteins. In this analysis of the charge distribution of 7 proteins, we estimate the solvation free energy contribution to the total free energy by exploring the 2(zeta) possible ionization states of the whole molecule, with zeta being the number of ionizable groups in the amino acid sequence, for every conformation in the ensembles of 7 proteins. As an additional consideration of the role of electrostatic interactions in determining the charge distribution of native folds, we carried out a comparison of alternative charge assignment models for the ionizable residues in a set of 21 native-like proteins.