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PubMed2002

The ATP-Mg2+ binding site and cytoplasmic domain interactions of Na+,K+-ATPase investigated with Fe2+-catalyzed oxidative cleavage and molecular modeling.

This work utilizes Fe(2+)-catalyzed cleavages and molecular modeling to obtain insight into conformations of cytoplasmic domains and ATP-Mg(2+) binding sites of Na(+),K(+)-ATPase. In E(1) conformations the ATP-Fe(2+) complex mediates specific cleavages at 712VNDS (P domain) and near 440VAGDA (N domain). In E(2)(K), ATP-Fe(2+) mediates cleavages near 212TGES (A domain), near 440VAGDA, and between residues 460-490 (N domain). Cleavages at high ATP-Fe(2+) concentrations do not support suggestions for two ATP sites. A new reagent, fluorescein-DTPA, has been synthesized. The fluorescein-DTPA-Fe(2+) complex mediates cleavages similar to those mediated by ATP-Fe(2+). The data suggest the existence of N to P domain interactions in E(1)Na, with bound ATP-Fe(2+) or fluorescein-DPTA-Fe(2+), A-N, and A-P interactions in E(2)(K), and provide testable constraints for model building. Molecular models based on the Ca(2+)-ATPase structure are consistent with the predictions. Specifically, high-affinity ATP-Mg(2+) binding in E(1) is explained with the N domain tilted ca. 80 degrees toward the P domain, by comparison with well-separated N and P domains in the Ca-ATPase crystal structure. With ATP-Mg(2+) docked, bound Mg(2+) is close to both D710 (in 710DGVNDS) and D443 (in 440VAGDASE). D710 is known to be crucial for Mg(2+) binding. The cleavage and modeling data imply that D443 could also be a candidate for Mg(2+) binding. Comparison of E(1).ATP,Mg(2+) and E(2) models suggests an explanation of the high or low ATP affinities, respectively. We propose a scheme of ATP-Mg(2+) and Mg(2+) binding and N, P, and A domain interactions in the different conformations of the catalytic cycle.

Adenosine Triphosphate↗
PubMed1995

Molecular modeling of the GM-CSF and IL-3 receptor complexes.

A model for the structure of the cytokine interleukin-3 (IL-3) is presented based on the structural homology of the hematopoietic cytokines and utilizing the crystal structures of interleukin-5 and granulocyte macrophage colony stimulating factor (GM-CSF). In addition, models of the receptor complexes of GM-CSF and IL-3 are presented based on the structural homology of the hematopoietic receptors to growth hormone. Several key interactions between the ligands and their receptors are discovered, some in agreement with previous mutagenesis studies and others that have not yet been the subject of mutagenesis studies. The models provide insights into the binding of GM-CSF and IL-3 to their receptors.

Amino Acid Sequence↗
PubMed2003

Molecular modeling studies on CNG channel from bovine retinal rod: a structural model of the cyclic nucleotide-binding domain.

A 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. In addition, it provides support for the rearrangement of the domain C helix on ligand binding and releasing proposed by Matulef et al. (Neuron 1999;24:443-452).

Animals↗
PubMed2005

A comparative molecular modeling study of dydrogesterone with other progestational agents through theoretical calculations and nuclear magnetic resonance spectroscopy.

6-Dehydroretroprogesterone (dydrogesterone) and three other natural or synthetic progestins (progesterone, retroprogesterone, and 6-dehydroprogesterone) were submitted to a conformational study through theoretical calculations at the B3LYP/6-31G(*) level and high field NMR spectroscopy. The study allows to define the role of the two structural features which differentiate these steroids, i.e., the C9 and C10 configuration and the C6-C7 unsaturation. The combined effects of the conformational preference of A ring, determined by the configuration at C9 and C10, and the enhanced rigidity due to the C6-C7 double bond, could account both for the higher activity and selectivity of dydrogesterone with respect to the other three steroids.

Chemical Phenomena↗
PubMed1996

Active site structure of Rieske-type proteins: electron nuclear double resonance studies of isotopically labeled phthalate dioxygenase from Pseudomonas cepacia and Rieske protein from Rhodobacter capsulatus and molecular modeling studies of a Rieske center.

Continuous wave electron nuclear double resonance (CW ENDOR) spectra of [delta-15N,epsilon(-14)N]histidine-labeled phthalate dioxygenase (PDO) from Pseudomonas cepacia were recorded and found to be virtually identical to those previously recorded from [delta,epsilon-15N2]histidine-labeled protein [Gurbiel, R. J., Batie, C. J., Sivaraja, M., True, A. E., Fee, J. A., Hoffman, B. M., & Ballou, D. P. (1989) Biochemistry 28, 4861-4871]. Thus, the two histidine residues, previously shown to ligate one of the irons in the cluster [cf. Gurbiel et al. 1989)], both coordinate the metal at the N(delta) position of their imidazole rings. Pulsed ENDOR studies showed that the "remote", noncoordinating nitrogen of the histidine imidazole ring could be observed from the Rieske protein in a sample of Rhodobacter capsulatus cytochrome bc1 complex uniformly labeled with 15N but not in a sample of PDO labeled with [delta-15N,epsilon-14N]histidine, but this atom was easily observed with a sample of Rh. capsulatus cytochrome bc1 complex that had been uniformly labeled with 15N; this confirmed the conclusion from the CW ENDOR studies that ligation is exclusively via N(delta) for both ligands in the PDO center. Modifications in the algorithms previously used to simulate 14N ENDOR spectra permitted us to compute spectra without any constraints on the relative orientation of hyperfine and quadrupole tensors. This new algorithm was used to analyze current and previously published spectra, and slightly different values for the N-Fe-N angle and imidazole ring rotation angles are presented [cf. Gurbiel et al. (1989) Gurbiel, R. J., Ohnishi, T., Robertson, D. E., Daldal, F., and Hoffman, B. M. (1991) Biochemistry 30, 11579-11584]. This analysis has permitted us to refine the proposed structure of the [2Fe-2S] Rieske-type cluster and rationalize some of the properties of these novel centers. Although the spectra of cytochrome bc1 complex from Rh. capsulatus are of somewhat lower resolution than those obtained with samples of PDO, our analysis nevertheless permits the conclusion that the geometry of the cluster is essentially the same for all Rieske and Rieske-type proteins. Structural constraints inferred from the spectroscopic results permitted us to apply the principles of distance geometry to arrive at possible three-dimensional models of the active site structure of Rieske protein from Rh. capsulatus. Results from this test case indicate that similar procedures should be generally useful in metalloprotein systems. We also recorded the pulsed and CW ENDOR spectra of 57Fe-labeled PDO, and the resulting data were used to derive the full hyperfine tensors for both Fe(III) and Fe(II) ions, including their orientations relative to the g tensor. The A tensor of the ferric ion is nominally isotropic, while the A tensor of the ferrous ion is axial, having A(parallel) > A(perpendicular); both tensors are coincident with the observed g tensor, with A(parallel) of the ferrous ion lying along the maximum g-value, g1. These results were examined using refinements of existing theories of spin-coupling in [2Fe-2S]+ clusters, and it is concluded that current theories are not adequate to fully describe the experimental results.

Acinetobacter calcoaceticus↗
PubMed1994

Molecular model of the A subunit of protein phosphatase 2A: interaction with other subunits and tumor antigens.

Protein phosphatase 2A consists of three subunits, the catalytic subunit (C) and two regulatory subunits (A and B). The A subunit has a rod-like shape and consists of 15 nonidentical repeats. It binds the catalytic subunit through repeats 11 to 15 at the C terminus and the tumor antigens encoded by small DNA tumor viruses through overlapping but distinct regions at N-terminal repeats 2 to 8. A model of the A subunit was developed on the basis of the fact that uncharged or hydrophobic amino acids are conserved at eight defined positions within each repeat. Helical wheel projections suggested that each repeat can be arranged as two interacting amphipathic helixes connected by a short loop. Mutational analysis of the A subunit revealed that the proposed loops are important for binding of tumor antigens, the B subunit, and the C subunit. Native gel analysis of mutant A subunits synthesized in vitro demonstrated that the binding region for the B subunit, previously thought to include repeats 2 to 8, covers repeats 1 to 10 and that the B and C subunits cooperate in binding to the A subunit.

Amino Acid Sequence↗
PubMed2006

A molecular model for epsilon-caprolactam-based intercalated polymer clay nanocomposite: Integrating modeling and experiments.

In studying the morphology, molecular interactions, and physical properties of organically modified montmorillonite (OMMT) and polymer clay nanocomposites (PCNs) through molecular dynamics (MD), the construction of the molecular model of OMMT and PCN is important. Better understanding of interaction between various constituents of PCN will improve the design of polymer clay nanocomposite systems. MD is an excellent tool to study interactions, which require accurate modeling of PCN under consideration. Previously, the PCN models were constructed by different researchers on the basis of specific criteria such as minimum energy configuration, density of the polymer clay nanocomposite, and so forth. However, in this article we describe the development of models combining experimental and conventional molecular modeling to develop models, which are more representative of true intercalated PCN systems. The models were used for studying the morphological interactions and physical properties. These studies gave useful information regarding orientation of organic modifiers, area of coverage of organic modifiers over the interlayer clay surface, interaction of organic modifiers with clay in OMMT, interaction among different constituents of PCN, conformational and density change, and actual proportion of mixing of polymer with clay in PCN. We have X-ray diffraction and photoacoustic Fourier transform infrared spectroscopy to verify the model.

Aluminum Silicates↗
PubMed1987

The catalytic mechanism of Escherichia coli aspartate carbamoyltransferase: a molecular modelling study.

Based on molecular modelling study, we propose that the reaction between L-aspartate an carbamoylphosphate, catalyzed by E. coli aspartate carbamoyltransferase, may proceed via a tetrahedral intermediate and that the breakdown of the intermediate is facilitated by an intramolecular proton transfer between the amino group of L-aspartate and a terminal phosphate oxygen of carbamoylphosphate.

Aspartate Carbamoyltransferase↗
PubMed2005

Humanization of an anti-human TNF-alpha antibody by variable region resurfacing with the aid of molecular modeling.

The murine monoclonal antibody Z12 is of therapeutic interest for its neutralizing biological activity against human tumor necrosis factor-alpha (hTNF-alpha). We attempted to humanize Z12 with variable domain resurfacing guided by computer modeling. First, the genes of heavy and light chain variable region (VH, VL) of Z12 were cloned and the whole three-dimensional structure of Fv fragment was constructed by using homology-based modeling and molecular docking methods. Then the complex model of Fv interacting with hTNF-alpha whose crystal structure derived from PDB database was gained with computer-guided docking program. Based on this model, a humanized version was designed. The humanized Fab antibody was constructed, expressed and purified in the pComb3H vector system and it showed unaltered binding affinity to the antigen as determined by ELISA and atomic force microscopy (AFM). The method described here can be used to humanize other anti-hTNF-alpha antibodies.

Amino Acid Sequence↗
PubMed1986

Structural aspects of drug-DNA complexes: molecular modelling of intercalative interactions.

The molecular aspects of drug-DNA interactions are presented, with special reference to anticancer drugs. The current status of, and results from, X-ray crystallographic studies on drug-oligonucleotide complexes are reviewed. The conformational features of these complexes are given in relation to the geometry of the drug binding site. Computerized molecular modelling for the rational analysis and design of DNA-binding drugs is discussed, taking the X-ray information as a starting point. Recent results from the author's laboratory on anthraquinones and anthracyclines are presented.

Animals↗
PubMed1991

Molecular modeling of proteins: a strategy for energy minimization by molecular mechanics in the AMBER force field.

Energy minimization is an important step in molecular modeling of proteins. In this study, we sought to develop a minimization strategy which would give the best final structures with the shortest computer time in the AMBER force field. In the all-atom model, we performed energy minimization of the melittin (mostly alpha-helical) and cardiotoxin (mostly beta-sheet and beta-turns) crystal structures by both constrained and unconstrained pathways. In the constrained path, which has been recommended in the energy minimization of proteins, hydrogens were relaxed first, followed by the side chains of amino acid residues, and finally the whole molecule. Despite the logic of this approach, however, the structures minimized by the unconstrained path fit the experimental structures better than those minimized by constrained paths. Moreover, the unconstrained path saved considerable computer time. We also compared the effects of the steepest descents and conjugate gradients algorithms in energy minimization. Previously, steepest descents has been used in the initial stages of minimization and conjugate gradients in the final stages of minimization. We therefore studied the effect on the final structure of performing an initial minimization by steepest descents. The structures minimized by conjugate gradients alone resembled the structures minimized initially by the steepest descents and subsequently by the conjugate gradients algorithms. Thus an initial minimization using steepest descents is wasteful and unnecessary, especially when starting from the crystal structure. Based on these results, we propose the use of an unconstrained path and conjugate gradients for energy minimization of proteins. This procedure results in low energy structures closer to the experimental structures, and saves about 70-80% of computer time. This procedure was applied in building models of lysozyme mutants. The crystal structure of native T4 lysozyme was mutated to three different mutants and the structures were minimized. The minimized structures closely fit the crystal structures of the respective mutants (less than 0.3 A root-mean-square, RMS, deviation in the position of all heavy atoms). These results confirm the efficiency of the proposed minimization strategy in modeling closely related homologs. To determine the reliability of the united atom approximation, we also performed all of the above minimizations with united atom models. This approximation gave structures with similar but slightly higher RMS deviations than the all-atom model, but gave further savings of 60-70% in computer time. However, we feel further investigation is essential to determine the reliability of this approximation.(ABSTRACT TRUNCATED AT 400 WORDS)

Algorithms↗
PubMed2001

Development of a pharmacophore model for histamine H3 receptor antagonists, using the newly developed molecular modeling program SLATE.

New molecular modeling tools were developed to construct a qualitative pharmacophore model for histamine H3 receptor antagonists. The program SLATE superposes ligands assuming optimum hydrogen bond geometry. One or two ligands are allowed to flex in the procedure, thereby enabling the determination of the bioactive conformation of flexible H3 antagonists. In the derived model, four hydrogen-bonding site points and two hydrophobic pockets available for binding antagonists are revealed. The model results in a better understanding of the structure-activity relationships of H3 antagonists. To validate the model, a series of new antagonists was synthesized. The compounds were designed to interact with all four hydrogen-bonding site points and the two hydrophobic pockets simultaneously. These ligands have high H3 receptor affinity, thereby illustrating how the model can be used in the design of new classes of H3 antagonists.

Animals↗
PubMed2006

Acetylcholinesterase: molecular modeling with the whole toolkit.

Molecular modeling efforts aimed at probing the structure, function and inhibition of the acetylcholinesterase enzyme have abounded in the last decade, largely because of the system's importance to medical conditions such as myasthenia gravis, Alzheimer's disease and Parkinson's disease, and well as its famous toxicological susceptibility to nerve agents. The complexity inherent in such a system with multiple complementary binding sites, critical dynamic effects and intricate mechanisms for enzymatic function and covalent inhibition, has led to an impressively diverse selection of simulation techniques being applied to the system, including quantum chemical mechanistic studies, molecular docking prediction of noncovalent complexes and their associated binding free energies, molecular dynamics conformational analysis and transport kinetics prediction, and quantitative structure activity relationship modeling to tie salient details together into a coherent predictive tool. Effective drug and prophylaxis design strategies for a complex target like this requires some understanding and appreciation for all of the above methods, thus it makes an excellent case study for multi-tiered pharmaceutical modeling. This paper reviews a sample of the more important studies on acetylcholinesterase and helps to elucidate their interdependencies. Potential future directions are introduced based on the special methodological needs of the acetylcholinesterase system and on emerging trends in molecular modeling.

Acetylcholinesterase↗
PubMed2000

A three-dimensional model of the delta-opioid pharmacophore: comparative molecular modeling of peptide and nonpeptide ligands.

A comparative molecular modeling study of delta-opioid ligands was performed under the assumption that potent peptide and nonpeptide agonists may have common three-dimensional (3D) arrangement of pharmacophore groups upon binding to the delta-receptor. Low-energy conformations of the agonists 7-spiroindanyloxymorphone (SIOM) and 2-methyl-4a-alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12a-alpha-octahydro-quinolino[2,3,3-g]isoquinoline (TAN-67), and a partial agonist oxomorphindole (OMI) were determined by high-temperature molecular dynamics (MD). A good spatial overlap was found for the pharmacophore groups of SIOM, TAN-67, and OMI, including the basic nitrogen, phenol hydroxyl, and two aromatic ring. Based on this overlap we proposed a 3D pharmacophore model for nonpeptide delta-opioid agonists with a distance of 7.0 +/- 1.3 A between the two aromatic rings and of 8.2 +/- 1.0 A between the nitrogen and phenyl ring. The potent and highly delta-opioid receptor selective agonist [(2S,3R)-TMT(1)]DPDPE, which shares global backbone constraints of the 14-membered disulfide cycle and a strong preference for the trans rotamer of the TMT(1) side chain, was chosen as a peptide template of the delta-opioid pharmacophore. Extensive MD simulations at 300 K with the AMBER force field were performed for [(2S,3R)-TMT(1)]DPDPE and the less potent [(2S, 3S)-TMT(1)]DPDPE analogue. Multiple MD trajectories were collected for each peptide starting from the x-ray structures of DPDPE and [L-Ala(3)]DPDPE and from models proposed in the literature. Low-energy MD conformations were filtered by the nonpeptide pharmacophore query and then directly superimposed with SIOM, OMI, and TAN-67. Two conformers of [(2S,3R)-TMT(1)]DPDPE that showed the best overlap with the nonpeptide pharmacophore (rms deviation </= 1. 0 A for N,O atoms and centroids of two aromatic rings) were selected as possible delta-receptor binding conformations. These conformations have similar backbone structures, and trans rotamers of the TMT(1) side-chain group. They are reasonably close to the crystal structure of [L-Ala(3)]DPDPE, and differ significantly from the crystal structure of DPDPE. The conformer with a gauche(-) rotamer of Phe(4) is most consistent with structure-activity relationships of delta-opioid peptides. The proposed 3D models were used for rational design of new nonpeptide delta-receptor ligands.

Analgesics↗
PubMed2004

Molecular structure-dynamics relationships in glassy poly(isophthalamide)s as revealed by wide angle x-ray scattering, dielectric loss spectroscopy, and molecular modelling.

The effect of molecular structure on the gamma relaxation dynamics has been studied in a set of aromatic poly(isophthalamide)s. This polymer family differ in the bridge group between phenylene rings [hexafluoroisopropylidene (C(CF(3))(2)) or ether] and also in the presence of t-butyl groups (C(CH(3))(3)) as pendant substituent on the five position of isophthalic ring. The results obtained from wide angle x-ray scattering in the glassy state indicated that both (C(CF(3))(2)) and (C(CH(3))(3)) groups favor the separation between chains, which is reflected on different interchain average distances. Dielectric experiments showed that both bulky groups favor the mobility in the glassy state. Molecular modelling methods were used to know the kind of molecular motions associated to the dielectric relaxation observed below the glass transition temperature.

Journal Article↗
PubMed1980

Interactive display of molecular models using a microcomputer system.

An interactive graphics display system (IGDS) which presents perspective views of wire frame models is described. The display unit is a microprocessor driven TERAK 8510a system with a grid of 320 . 240 points. A brief discussion of the hardware is given. While the system is quite general - it can draw a perspective view of any type of wire frame model - emphasis here is on molecular models. The graphics software has been written in UCSD PASCAL. The program employs traditional computer graphics algorithms available in the literature, The data structure used by the program was designed to occupy minimal disk storage space. Data files can be constructed locally or can obtained through a communications link with with a central computer facility. Despite the inherent slowness (due to matrix operations being performed by the software calculations rather than hardware), the low cost of the system suggests general applicability. The program is easy to use, interactive, and produces good results from systems up to 200 points.

Computers↗
PubMed2004

Molecular modeling of B-DNA site recognition by Ru intercalators: molecular shape selection.

In this work, molecular modeling methods have been applied to the interaction characterization of polypyridyl transitional-metal complexes with the oligonucleotide (B-DNA fragment). In order to explore the factors governing the groove recognition and intercalative depth, we establish a simple and practical docking method (step-by-step docking operation) to obtain potential curves while making complexes inset into B-DNA along an assigned path. Energy values in the potential curve are obtained from energy minimization of binding geometries. Modeling results clearly show that the optimum binding conformation corresponding to the global minimum in the potential curve for each complex is found to correlate well with the experimental results. Our results also confirm that minor changes of the ligand structure can lead to profound influences on binding geometries, so the molecular shape of the complexes is a predominant factor in governing the binding mode. Moreover, we find that the vdW force and "water molecular effect" are strongly associated with molecular-shape selection in our model. These results complement and extend the knowledge of the nature of these complexes binding to B-DNA.

Computer Simulation↗