Structure and dynamics of substrate binding (cefotaxime) to the catalytic pocket of the mononuclear zinc-beta-lactamase from Bacillus cereus are investigated by molecular dynamics simulations. The calculations, which are based on the hydrogen-bond pattern recently proposed by Dal Peraro et al. (J Biol Inorg Chem 2002; 7:704-712), are carried out for both the free and the complexed enzyme.
View Article and Find Full Text PDFMolecular dynamics simulations are used to investigate dynamics and intramolecular interactions of the HIV-1 transactivator (Tat) in aqueous solution. The calculations are based on the AMBER force field with particle mesh Ewald treatment for long-range electrostatics. The Tat structure exhibits a large flexibility, consistent with its absence of secondary structure elements.
View Article and Find Full Text PDF(alpha3)2(beta4)3 is the most abundant type of neuronal nicotinic ACh receptor (nAChR) mediating cholinergic actions on the autonomic nervous system. Studies to refine or devise drugs selectively acting on (alpha3)2(beta4)3 receptors would benefit from a detailed description of the hitherto unclear agonist-binding domain. The present study reports a three-dimensional model for the ligand-binding domain (LBD) of this receptor either in its unoccupied or agonist-bound conformation.
View Article and Find Full Text PDFA dimeric model of the cyclic nucleotide-binding domain of the all-alpha homomeric cyclic nucleotide-gated channel from bovine retinal rod is constructed. The model, based on the structure of the fairly homologous catabolite gene activator protein (Weber and Steitz, J Mol Biol 1987;198:311-326), is obtained by use of comparative modeling and molecular dynamics simulations. Our model provides a structural basis for the experimentally measured difference in activity between cAMP and cGMP, as well as the different solvent accessibilities of GLY597 in the complex with cGMP, with cAMP and in the protein in free state.
View Article and Find Full Text PDFThe determination of the protonation state of enzyme active sites may be crucial for the investigation of their mechanism of action. In the bizinc beta-lactamase family of enzymes, no consensus has been reached on the protonation state of a fully conserved amino acid present in the active site, Asp120. To address this issue, we carry out here density functional theory (DFT) calculations on large models (based on Bacteroides fragilis X-ray structure) which include the metal coordination polyhedron and groups interacting with it.
View Article and Find Full Text PDFThe nerve growth factor (NGF) is an important pharmacological target for Alzheimer's and other neurodegenerative diseases. Its action derives partly from its binding to the tyrosine kinase A receptor (TrkA). Here we study energetics and dynamics of the NGF-TrkA complex by carrying out multinanosecond molecular dynamics simulations, accompanied by electrostatic calculations based on the Poisson-Boltzmann equation.
View Article and Find Full Text PDFRecent advances in membrane protein crystallography have greatly increased structural information of channels permeating metal ions. Structural bioinformatics techniques and molecular dynamics calculations are providing structural models of ion channels for which the three-dimensional structure is not known. Most of the reported structure prediction studies focus on K(+) channels and are based on the KcsA K(+) channel structure.
View Article and Find Full Text PDFJ Recept Signal Transduct Res
June 2003
Extracellular tetraethylammonium (TEA+) inhibits the current carried out by K+ ions in potassium channels. Structural models of wild-type (WT) and Y82C KcsA K+ channel/TEA+ complexes are here built using docking procedures, electrostatics calculations and molecular dynamics simulations. The calculations are based on the structure determined by Doyle et al.
View Article and Find Full Text PDFSarcoplasmic reticulum Ca(2+)- ATPase pumps Ca(2+) ions from muscle cells to the sarcoplasmic reticulum. Here we use molecular dynamics and electrostatic modeling to investigate structural and dynamical features of key intermediates in the Ca(2+) binding process of the protein. Structural models of the protein (containing either two, one, or no calcium ions in the transmembrane domain) are constructed based on the X-ray structure by Toyoshima et al.
View Article and Find Full Text PDFThe emergence of drug-resistant variants is a serious side effect associated with acquired immune deficiency syndrome therapies based on inhibition of human immunodeficiency virus type 1 protease (HIV-1 PR). In these variants, compensatory mutations, usually located far from the active site, are able to affect the enzymatic activity via molecular mechanisms that have been related to differences in the conformational flexibility, although the detailed mechanistic aspects have not been clarified so far. Here, we perform multinanosecond molecular dynamics simulations on L63P HIV-1 PR, corresponding to the wild type, and one of its most frequently occurring compensatory mutations, M46I, complexed with the substrate and an enzymatic intermediate.
View Article and Find Full Text PDFThe electronic properties of a Z-DNA crystal synthesized in the laboratory are investigated by means of density-functional theory Car-Parrinello calculations. The electronic structure has a gap of only 1.28 eV.
View Article and Find Full Text PDFZinc(II)-beta-lactamases are among the latest generation of antibiotic-resistant enzymes developed by bacteria against beta-lactams. Here we have used density functional theory to provide the full structure of the catalytic site from Bacillus cereus mononuclear beta-lactamase II. Calculations are carried out on relative large models built on the X-ray structure of the free enzyme at the highest available resolution (1.
View Article and Find Full Text PDFTat is an essential protein of the human immunodeficiency virus type 1 (HIV-1). It activates transcription by specifically binding a stem-loop element in the viral long terminal repeat through its highly basic arginine-rich domain. Conserved lysine residues at positions 50 and 51 inside this domain have been recently reported to be the targets of post-translational modification by acetylation, and mutation of these residues has pointed out its relevance to protein function.
View Article and Find Full Text PDFAb initio molecular dynamics (MD) allows realistic simulations to be performed without adjustable parameters. In recent years, the technique has been used on an increasing number of applications to biochemical systems. Here we describe the principles on which ab initio MD is based.
View Article and Find Full Text PDFThe emergence of compensatory drug-resistant mutations in HIV-1 protease challenges the common view of the reaction mechanism of this enzyme. Here, we address this issue by performing classical and ab initio molecular dynamics simulations (MD) on a complex between the enzyme and a peptide substrate. The classical MD calculation reveals large-scale protein motions involving the flaps and the cantilever.
View Article and Find Full Text PDFBiochim Biophys Acta
June 2002
We present a theoretical study on structural and electronic aspects of K+ permeation through the binding sites of the KcsA channel's selectivity filter. Density functional calculations are carried out on models taken from selected snapshots of a molecular dynamics simulation recently reported [FEBS Lett. 477 (2000) 37].
View Article and Find Full Text PDFAb initio methods were used to shed light on fundamental aspects of the enzymatic mechanism of guanosine triphosphate hydrolysis in the Cdc42/Cdc42GAP complex. The calculations focused on the nucleophilic addition of the catalytic water molecule to the gamma-phosphate phosphorus atom. A large model system was required to correctly reproduce the electrostatic properties on the active site.
View Article and Find Full Text PDFWe present an ab initio molecular dynamics study of the complex between acyl carrier protein reductase InhA from M. tuberculosis and isonicotinic acid hydrazide-NADH. We focus on wild-type (WT) InhA and a mutant causing drug resistance (S94A) for which structural information is available (Rozwarski et al.
View Article and Find Full Text PDFPeptides related to the N-terminal region of calcitonin gene-related peptide (CGRP) were tested for their ability to modulate neuronal nicotinic acetylcholine receptors (nAChRs) of rat cultured chromaffin cells under whole cell patch-clamp conditions. Although CGRP(1-7) and CGRP(2-7) depressed responses mediated by nAChRs, CGRP(1-6), CGRP(1-5), or CGRP(1-4) rapidly and reversibly potentiated submaximal nicotine currents while sparing maximal currents. CGRP(1-3) was inactive.
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