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PubMed2005

Theoretically predicted structures of plasma membrane Ca(2+)-ATPase and their susceptibilities to oxidation.

Oxidative damage to the plasma membrane Ca(2+)-ATPase (PMCA) appears to contribute to the decreased clearance of intracellular Ca(2+) in the neurons of aged brain, possibly contributing to its vulnerability to numerous age-related diseases such as Alzheimer's disease. The precise sites of oxidative susceptibility have not been identified. However, it is known that calmodulin (CaM) protects the purified PMCA against oxidative inactivation, perhaps via conformational restructuring of the protein through dissociation of a 20 residue domain (C20W) in the C-terminal region that function as a CaM-binding site. In order to postulate likely oxidation sites and the mechanism underlying the protection offered by CaM, we have generated a three-dimensional model of PMCA via a combination of homology/comparative modeling, threading, protein-protein docking, and guidance from prior biochemical and analytical studies. The resulting model was validated based on surface polarity/hydrophobicity profiling, standard ProCheck, WhatIF, and PROVE checks, as well as comparison with empirical structure-function observations. This model was then used to identify likely oxidation sites by comparing time-averaged solvent accessibility of potentially oxidizable surface residues as measured from molecular dynamics simulations of intact PMCA and the PMCA sequence from which C20W has been deleted. The resulting model complex has permitted us to identify three amino acids whose solvent accessibility is greatly reduced by the C20W dissociation: Tyr 589, Met 622, and Met 831.

Adenosine Triphosphate↗

PubMed2004

Relative free energy of binding and binding mode calculations of HIV-1 RT inhibitors based on dock-MM-PB/GS.

Tetrahydroimidazo-[4,5,l-jk][1,4]-benzodiazepin-2-(1H)-one (TIBO) derivatives are important nonnucleoside human immunodeficiency virus-1 reverse transcriptase inhibitors (NNRTI). Several TIBO derivatives have shown high potency to inhibit reverse transcriptase (RT) and one (Tivirapine) has entered into clinical trials. The free energy of binding (FEB) is a numerical way to express the binding affinity of a ligand to its receptor and has been applied in screening candidates in rational drug design. In this work, the FEB of 42 TIBOs in RT was studied. Relative FEB is expressed in the form of a linear combination of vdW, electrostatic, solvation, and nonpolar solvation energy terms. The predicted FEB activity of the TIBOs studied has a good correlation (r(2) = 0.8680, q(2) = 0.8298) with respect to the experimental activity (pIC(50)). Based on the data reported here, the Finite Difference Poisson Boltzmann with a Gaussian Smooth Dielectric Constant Function method (PB/GS) solvation energy term is very important in predicting the binding affinity of TIBOs in RT. In summary, the Dock-Molecular Mechanics (MM)-PB/GS method is a promising technique in predicting ligand/receptor binding affinity and it can be used to screen relatively large sets of molecules in a reasonable amount of computer time.

Anti-HIV Agents↗

PubMed1999

Interaction of mitochondrial presequences with DnaK and mitochondrial hsp70.

Mitochondrial heat shock protein 70 (mt-hsp70) functions as a molecular chaperone in mitochondrial biogenesis. The chaperone in co-operation with its co-proteins acts as a translocation motor pulling the mitochondrial precursor into the matrix. Mt-hsp70s are highly conserved when compared to the bacterial hsp70 homologue, DnaK. Here we have used DnaK as a model to study the interaction of mitochondrial presequences with mt-hsp70 applying a DnaK-binding algorithm, computer modeling and biochemical investigations. DnaK-binding motifs have been analysed on all available, statistically relevant mitochondrial presequences found in the OWL database by running the algorithm. A total of 87 % of mammalian, 97 % of plant, 71 % of yeast and 100 % of Neurospora crassa presequences had at least one DnaK binding site. Based on the prediction, five 13-mer presequence peptides have been synthesized and their inhibitory effect on the molecular chaperone (DnaK/DnaJ/GrpE) assisted refolding of luciferase has been analysed. The peptide with the highest predicted binding likelihood showed the strongest inhibitory effect, whereas the peptide with no predicted binding capacity showed no inhibitory effect. A 3D structure of the pea mt-hsp70 has been constructed using homology modeling. The binding affinities of the 13-mer presequence peptides and additional control peptides to DnaK and pea mt-hsp70 have been theoretically estimated by calculating the buried hydrophobic surface area of the peptides docked to DnaK and to the mt-hsp70 structural model. These results suggest that mitochondrial presequences interact with the mt-hsp70 during or after mitochondrial protein import.

Amino Acid Sequence↗

PubMed2005

Progress in computation and amide hydrogen exchange for prediction of protein-protein complexes.

The macromolecular docking problem that must be solved for experimental biologists is prediction of the structures of complexes for which the components are known or reliably modeled in the unbound state, but the structure of the complex is unknown. The current state of the art in macromolecular docking is such that solving this problem usually requires supplementary experimental chemical and/or biological information to evaluate computational predictions. Amide (1)H/(2)H exchange measured by mass spectroscopy is a promising approach for obtaining such information, because it can reveal interfacial regions of each member of the complex and identify regions of conformational flexibility in the structure. In a previous article (Anand et al., Proc Natl Acad Sci USA 2003;100:13264-13269), we used (1)H/(2)H exchange data to predict the structure of a complex between regulatory and catalytic subunits of protein kinase A. Comparison of the prediction with a recent crystal structure determination (Kim et al., Science 2005;307:690-696) showed large conformational change in the regulatory subunit on formation of the complex. Analysis of the prediction, previous CAPRI results, novel data processing methods for the (1)H/(2)H exchange data, and new fragment docking computations give grounds for cautious optimism that this method can be useful even in cases of substantial conformational change.

Algorithms↗

PubMed2005

Global rigid body modeling of macromolecular complexes against small-angle scattering data.

New methods to automatically build models of macromolecular complexes from high-resolution structures or homology models of their subunits or domains against x-ray or neutron small-angle scattering data are presented. Depending on the complexity of the object, different approaches are employed for the global search of the optimum configuration of subunits fitting the experimental data. An exhaustive grid search is used for hetero- and homodimeric particles and for symmetric oligomers formed by identical subunits. For the assemblies or multidomain proteins containing more then one subunit/domain per asymmetric unit, heuristic algorithms based on simulated annealing are used. Fast computational algorithms based on spherical harmonics representation of scattering amplitudes are employed. The methods allow one to construct interconnected models without steric clashes, to account for the particle symmetry and to incorporate information from other methods, on distances between specific residues or nucleotides. For multidomain proteins, addition of missing linkers between the domains is possible. Simultaneous fitting of multiple scattering patterns from subcomplexes or deletion mutants is incorporated. The efficiency of the methods is illustrated by their application to complexes of different types in several simulated and practical examples. Limitations and possible ambiguity of rigid body modeling are discussed and simplified docking criteria are provided to rank multiple models. The methods described are implemented in publicly available computer programs running on major hardware platforms.

Algorithms↗

PubMed2005

Computer simulation of protein-ligand interactions: challenges and applications.

The accurate modeling of protein-ligand interactions, like any prediction of macromolecular structure, requires an energy function of sufficient detail to account for all relevant interactions and a conformational search method that can reliably find the energetically favorable conformations of a heterogeneous system. Both of these prerequisites represent daunting challenges. Consequently, the routine docking of small molecules or peptides to proteins in their correct binding modes, and the reliable ranking of binding affinities remain unsolved problems. Nonetheless, computational techniques are continually evolving so as to broaden the range of feasible applications, and the accuracy of predictions and theoretical approaches can often be of great help in guiding and interpreting experiments. We discuss the energetics of protein-ligand systems and survey conformational searching techniques. We illustrate how molecular modeling of a protein-ligand complex sheds light on the observed resistance of a mutant dihydrofolate reductase to the antibiotic trimethoprim. In another example, we show that relaxation of side chains in different crystal structures of the same complex, benzamidine bound to trypsin, is needed to draw sensible conclusions from the calculations. The results of these relatively simple conformational searches underscore the importance of incorporating protein flexibility in simulations of protein-ligand interactions, even in the context of relatively rigid binding pockets.

Animals↗

PubMed2004

Computational design of receptors for an organophosphate surrogate of the nerve agent soman.

We report the computational design of soluble protein receptors for pinacolyl methyl phosphonic acid (PMPA), the predominant hydrolytic product of the nerve agent soman. Using recently developed computational protein design techniques, the ligand-binding pockets of two periplasmic binding proteins, glucose-binding protein and ribose-binding protein, were converted to bind PMPA instead of their cognate sugars. The designs introduce 9-12 mutations in the parent proteins. Twelve of 20 designs tested exhibited PMPA-dependent changes in emission intensity of a fluorescent reporter with affinities between 45 nM and 10 microM. The contributions to ligand binding by individual residues were determined in two designs by alanine-scanning mutagenesis, and are consistent with the molecular models. These results demonstrate that designed receptors with radically altered binding specificities and affinities that rival or exceed those of the parent proteins can be successfully predicted. The designs vary in parent scaffold, sequence diversity, and orientation of docked ligand, suggesting that the number of possible solutions to the design problem is large and degenerate. This observation has implications for the genesis of biological function by random processes. The designed receptors reported here may have utility in the development of fluorescent biosensors for monitoring nerve agents.

Binding Sites↗

PubMed1999

3D modeling, ligand binding and activation studies of the cloned mouse delta, mu; and kappa opioid receptors.

Refined 3D models of the transmembrane domains of the cloned delta, mu and kappa opioid receptors belonging to the superfamily of G-protein coupled receptors (GPCRs) were constructed from a multiple sequence alignment using the alpha carbon template of rhodopsin recently reported. Other key steps in the procedure were relaxation of the 3D helix bundle by unconstrained energy optimization and assessment of the stability of the structure by performing unconstrained molecular dynamics simulations of the energy optimized structure. The results were stable ligand-free models of the TM domains of the three opioid receptors. The ligand-free delta receptor was then used to develop a systematic and reliable procedure to identify and assess putative binding sites that would be suitable for similar investigation of the other two receptors and GPCRs in general. To this end, a non-selective, 'universal' antagonist, naltrexone, and agonist, etorphine, were used as probes. These ligands were first docked in all sites of the model delta opioid receptor which were sterically accessible and to which the protonated amine of the ligands could be anchored to a complementary proton-accepting residue. Using these criteria, nine ligand-receptor complexes with different binding pockets were identified and refined by energy minimization. The properties of all these possible ligand-substrate complexes were then examined for consistency with known experimental results of mutations in both opioid and other GPCRs. Using this procedure, the lowest energy agonist-receptor and antagonist-receptor complexes consistent with these experimental results were identified. These complexes were then used to probe the mechanism of receptor activation by identifying differences in receptor conformation between the agonist and the antagonist complex during unconstrained dynamics simulation. The results lent support to a possible activation mechanism of the mouse delta opioid receptor similar to that recently proposed for several other GPCRs. They also allowed the selection of candidate sites for future mutagenesis experiments.

Amino Acid Sequence↗

PubMed2005

Computational studies of the reversible domain swapping of p13suc1.

A minimalist representation of protein structures using a Go-like potential for interactions is implemented to investigate the mechanisms of the domain swapping of p13suc1, a protein that exists in two native conformations: a monomer and a domain-swapped dimer formed by the exchange of a beta-strand. Inspired by experimental studies which showed a similarity of the transition states for folding of the monomer and the dimer, in this study we justify this similarity in molecular descriptions. When intermediates are populated in the simulations, formation of a domain-swapped dimer initiates from the ensemble of unfolded monomers, given by the fact that the dimer formation occurs at the folding/unfolding temperature of the monomer (T(f)). It is also shown that transitions, leading to a dimer, involve the presence of two intermediates, one of them has a dimeric form and the other is monomeric; the latter is much more populated than the former. However, at temperatures lower than T(f), the population of intermediates decreases. It is argued that the two folded forms may coexist in absence of intermediates at a temperature much lower than T(f). Computational simulations enable us to find a mechanism, "lock-and-dock", for domain swapping of p13suc1. To explore the route toward dimer formation, the folding of unstructured monomers must be retarded by first locking one of the free ends of each chain. Then, the other free termini could follow and dock at particular regions, where most intrachain contacts are formed, and thus define the transition states of the dimer. The simulations also showed that a decrease in the maximum distance between monomers increased their stability, which is explained based on confinement arguments. Although the simulations are based on models extracted from the native structure of the monomer and the dimer of p13suc1, the mechanism of the domain-swapping process could be general, not only for p13suc1.

Binding Sites↗

PubMed2006

GRAMM-X public web server for protein-protein docking.

Protein docking software GRAMM-X and its web interface (http://vakser.bioinformatics.ku.edu/resources/gramm/grammx) extend the original GRAMM Fast Fourier Transformation methodology by employing smoothed potentials, refinement stage, and knowledge-based scoring. The web server frees users from complex installation of database-dependent parallel software and maintaining large hardware resources needed for protein docking simulations. Docking problems submitted to GRAMM-X server are processed by a 320 processor Linux cluster. The server was extensively tested by benchmarking, several months of public use, and participation in the CAPRI server track.

Binding Sites↗

PubMed2002

Molecular dynamics and free energy analyses of cathepsin D-inhibitor interactions: insight into structure-based ligand design.

In this study, we compare the calculated and experimental binding free energies for a combinatorial library of inhibitors of cathepsin D (CatD), an aspartyl protease. Using a molecular dynamics (MD)-based, continuum solvent method (MM-PBSA), we are able to reproduce the experimental binding affinity for a set of seven inhibitors with an average error of ca. 1 kcal/mol and a correlation coefficient of 0.98. By comparing the dynamical conformations of the inhibitors complexed with CatD with the initial conformations generated by CombiBuild (University of California, San Francisco, CA, 1995), we have found that the docking conformation observed in an X-ray structure of one peptide inhibitor bound to CatD (Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 6796-6800) is in good agreement with our MD simulation. However, the DOCK scoring function, based on intermolecular van der Waals and electrostatics, using a distance-dependent dielectric constant (J. Comput. Chem. 1992, 13, 505-524), poorly reproduces the trend of experimental binding affinity for these inhibitors. Finally, the use of PROFEC (J. Comput.-Aided Mol. Des. 1998, 12, 215-227) analysis allowed us to identify two possible substitutions to improve the binding of one of the better inhibitors to CatD. This study offers hope that current methods of estimating the free energy of binding are accurate enough to be used in a multistep virtual screening protocol.

Algorithms↗

PubMed1995

Docking of congo red to the surface of crystalline cellulose using molecular mechanics.

A method for the docking of ligands to crystalline surfaces using molecular mechanics was developed and applied to study the molecular features of the adsorption of Congo Red to cellulose crystals. The docking procedure was based on a grid search exploring the surface repeat unit of the cellulose crystals using several orientations of Congo Red at each grid point. Results suggest a preferential adsorption of Congo Red onto certain faces of the cellulose crystals and that the lower energy conformers have a similar positioning and orientation with respect to the cellulose chains at the surface repeat unit.

Adsorption↗

PubMed1996

Fitting an inhibitor into the active site of thermolysin: a molecular dynamics case study.

We used molecular dynamics computer simulation to "fly" a small flexible ligand, L-leucine hydroxamic acid, into the active site of thermolysin. The potential, which imposed no constraints between protein and ligand, produced conformations close to the crystallographically determined one. The calculations made use of the combined molecular mechanics/grid method of Luty et al. (J. Comp. Chem. 16:454-464, 1995), in which atoms of the active site are free to move whereas the rest of the protein, assumed to be rigid, is represented as points of a grid, and which also includes an implicit solvation model. The method is sufficiently fast that large sets of simulations could be carried out, enabling statistical sampling and exploration of the effect of initial position and conformation of the ligand on the probability of successful docking. In a charged catalytic Glu/uncharged ligand regime, when the initial position of the ligand was determined by random translations and rotations that kept the center of mass within 8.0 angstroms of the crystal one, none of the 20 runs placed the ligand correctly. In a second set with uncharged Glu and zwitterionic ligand, 3 of 24 similarly placed random structures flew the ligand in successfully. In a third set with the same protonation scheme as the second the starting positions had randomly determined conformations but kept the hydroxamate oxygens within 4.0 angstroms of the zinc; in this case 22 of 25 runs reoriented correctly. A diverse set of energetic, structural, and dynamic criteria was used for evaluation of the calculations. The results indicate the method to be a promising tool for the rational drug design process.

Binding Sites↗

PubMed2005

Molecular models of the procoagulant factor VIIIa-factor IXa complex.

BACKGROUND: Formation of the intrinsic tenase complex is an essential event in the procoagulant reactions that lead to clot formation. The tenase complex is formed when the activated serine protease, Factor IXa (FIXa), and its cofactor Factor VIIIa (FVIIIa) assemble on a phospholipid surface to proteolytically convert the zymogen Factor X (FX) into its active form FXa. The physiological relevance of the tenase complex is evident in hemophilia A or B patients who present with bleeding disorders. OBJECTIVES: The purpose of this study was to establish three-dimensional (3D) models of the FVIIIa-FIXa complex. METHODS: First, we built two new theoretical models of FVIIIa via homology modeling, inter-domain docking and loop simulation algorithms as well as a model for FIXa. This was followed by pseudo-Brownian protein-protein docking in internal coordinates with the ICM (Internal Coordinates Mechanics) program between the two FVIIIa and the FIXa structures. RESULTS: Ten representative models of this complex are presented based on agreements with known experimental data and according to structural criteria. CONCLUSIONS: These novel 3D models will help guide future site directed mutagenesis aimed at improving the functionality of FVIIIa and/or FIXa and will contribute to a better understanding of the role of this macromolecular complex in the blood coagulation cascade.

Algorithms↗

PubMedDate not supplied

Using situs for flexible and rigid-body fitting of multiresolution single-molecule data.

We describe here a set of multiresolution visualization and docking procedures that we refer to as the Situs package. The package was developed to provide an efficient and robust method for the fitting of atomic structures into low-resolution data. The current release was optimized specifically for the visualization and docking of single molecules. A novel 3D graphics viewer, volslice3d, was developed for the package to provide an immersive virtual reality environment for measuring and rendering volumetric data sets. The precision of single-molecule, rigid-body docking was tested on simulated (noise-free) low-resolution density maps. For spatial resolutions near 20 A typically arising in electron microscopy image reconstructions, a docking precision on the order of 1 A can be achieved. The shape-matching score captured the correct solutions in all 10 trial cases and was sufficiently stringent to yield unique matches in 8 systems. Novel routines were developed for the flexible docking of atomic structures whose shape deviates from the corresponding low-resolution shape. Test calculations on isoforms of actin and lactoferrin demonstrate that the flexible docking faithfully reproduces conformational differences with a precision < 2 A if atomic structures are locally conserved.

Actins↗

PubMed2003

Structural modeling of the Lhca4 Subunit of LHCI-730 peripheral antenna in photosystem I based on similarity with LHCII.

Peripheral chlorophyll a/b binding antenna of photosystem I (LHCI) from green algae and higher plants binds specific low energy absorbing chlorophylls (red pigments) that give rise to a unique red-shifted emission. A three-dimensional structural model of the Lhca4 polypeptide from the LHCI from higher plants was constructed on the basis of comparative sequence analysis, secondary structure prediction, and homology modeling using LHCII as a template. The obtained model of Lhca4 helps to visualize protein ligands to nine chlorophylls (Chls) and three potential His residues to extra Chls. Central domain of the Lhca4 comprising the first (A) and the third (C) transmembrane (TM) helices that binds 6 Chl molecules and two carotenoids is conserved structurally, whereas the interface between the first and the second TM helices and the outer surface of the second TM helix differ significantly among the LHCI and LHCII polypeptides. The model of Lhca4 predicts a histidine residue in the second TM helix, a potential binding site for extra Chl in close proximity to Chls a5 and b5 (labeling by Kühlbrandt). The interpigment interactions in the formed pigment cluster are suggested to cause a red spectral shift in absorption and emission. Modeling of the LHCI-730 heterodimer based on the model structures of Lhca1 and Lhca4 allowed us to suggest potential sites of pigment-pigment interactions that might be formed upon heterodimerization or docking of the LHCI dimers to the surface of PSI.

Amino Acid Sequence↗

PubMed1997

Structure-based discovery of ligands targeted to the RNA double helix.

Ligands capable of specific recognition of RNA structures are of interest in terms of the principles of molecular recognition as well as potential chemotherapeutic applications. We have approached the problem of identifying small molecules with binding specificity for the RNA double helix through application of the DOCK program [Kuntz, I. D., Meng, E. C., and Shoichet, B. K. (1994) Acc. Chem. Res. 27, 117-123], a structure-based method for drug discovery. A series of lead compounds was generated through a database search for ligands with shape complementarity to the RNA deep major groove. Compounds were then evaluated with regard to their fit into the minor groove of B DNA. Those compounds predicted to have an optimal fit to the RNA groove and strong discrimination against DNA were examined experimentally. Of the 11 compounds tested, 3, all aminoglycosides, exhibited pronounced stabilization of RNA duplexes against thermal denaturation with only marginal effects on DNA duplexes. One compound, lividomycin, was examined further, and shown to facilitate the ethanol-induced B to A transition in calf thymus DNA. Fluorine NMR solvent isotope shift measurements on RNA duplexes containing 5-fluorouracil provided evidence that lividomycin binds in the RNA major groove. Taken together, these results indicate that lividomycin recognizes the general features of the A conformation of nucleic acids through deep groove binding, confirming the predictions of our DOCK analysis. This approach may be of general utility for identifying ligands possessing specificity for additional RNA structures as well as other nucleic acid structural motifs.

Aminoglycosides↗

PubMed2006

Rational design of a nonpeptide general chemical scaffold for reversible inhibition of PDZ domain interactions.

Novel small molecules were designed to specifically target the ligand-binding pocket of a PDZ domain. Iterative molecular docking and modeling allowed the design of an indole scaffold 10a as a reversible inhibitor of ligand binding. The 10a scaffold inhibited the interaction between MAGI-3 and PTEN and showed cellular activities that are consistent with the inhibition of NHERF-1 function.

Adaptor Proteins, Signal Transducing↗