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PubMed2003

Docking and electron transfer studies between rubredoxin and rubredoxin:oxygen oxidoreductase.

The interaction and electron transfer (ET) between rubredoxin (Rd) and rubredoxin:oxygen oxidoreductase (ROO) from Desulfovibrio gigas is studied by molecular modelling techniques. Experimental kinetic assays using recombinant proteins show that the Rd reoxidation by ROO displays a bell-shaped dependence on ionic strength, suggesting a non-trivial electrostatic dependence of the interaction between these two proteins. Rigid docking studies reveal a prevalence for Rd to interact, in a very specific way, with the surface of the ROO dimer near its FMN cofactors. The optimization of the lowest energy complexes, using molecular dynamics simulation, shows a very tight interaction between the surface of the two proteins, with a high probability for Rd residues (but not the iron centre directly) to be in direct contact with the FMN cofactors of ROO. Both electrostatics and van der Waals interactions contribute to the final energy of the complex. In these complexes, the major contributions for complex formation are polar interactions between acidic residues of Rd and basic residues of ROO, plus substantial non-polar interactions between different groups. Important residues for this process are identified. ET estimates (using the Pathways model), in the optimized lowest energy complexes, suggest that these configurations are efficient for transferring electrons. The experimental bell-shaped dependence of kinetics on ionic strength is analysed in view of the molecular modelling results, and hypotheses for the molecular basis of this phenomenon are discussed.

Amino Acid Sequence↗
PubMed2006

Nucleotide channel of RNA-dependent RNA polymerase used for intermolecular uridylylation of protein primer.

Poliovirus VPg is a 22 amino acid residue peptide that serves as the protein primer for replication of the viral RNA genome. VPg is known to bind directly to the viral RNA-dependent RNA polymerase, 3D, for covalent uridylylation, yielding mono and di-uridylylated products, VPg-pU and VPg-pUpU, which are subsequently elongated. To model the docking of the VPg substrate to a putative VPg-binding site on the 3D polymerase molecule, we performed a variety of structure-based computations followed by experimental verification. First, potential VPg folded structures were identified, yielding a suite of predicted beta-hairpin structures. These putative VPg structures were then docked to the region of the polymerase implicated by genetic experiments to bind VPg, using grid-based and fragment-based methods. Residues in VPg predicted to affect binding were identified through molecular dynamics simulations, and their effects on the 3D-VPg interaction were tested computationally and biochemically. Experiments with mutant VPg and mutant polymerase molecules confirmed the predicted binding site for VPg on the back side of the polymerase molecule during the uridylylation reaction, opposite to that predicted to bind elongating RNA primers.

Amino Acid Sequence↗
PubMed1996

The rationale for E2020 as a potent acetylcholinesterase inhibitor.

The phase III drug-candidate, E2020, developed for treatment of Alzheimer's disease, and possibly other demenitas, and its analogues have been the focus of extensive molecular pharmacological and structural studies. The potency and selectivity of E2020 as an inhibitor of acetylcholinesterase, AChE, in the brain is established. A combination of molecular modeling and QSAR studies have been used throughout the evolution of the AChE inhibitor program leading to the benzylpiperidine series, and, ultimately, E2020. QSAR studies have identified requirements of optimize inhibition activity as a function of substituent choice on both the indanone and benzyl rings in the E2020 class of inhibitors. A combination of X-ray crystal structure studies of E2020 isomers and the molecular shape analysis, MSA, of E2020 and its analogues has led to a postulated active conformation, and molecular shape, for these AChE inhibitors. The active molecular shape corresponds to a high degree of shape similarity between the two E2020 isomers which, in turn, is consistent with the observed high inhibition potencies of both of these compounds. Intermolecular docking studies were carried out for E2020 and some analogues with the crystal structure of AChE when it became available. The docking simulations involving E2020 analogues suggest these inhibitors do not bind at the acetylcholine, ACh, active site, but rather at the most narrow location of the long channel leading to the active site. Intermolecular binding geometries are consistent with the postulated active conformations derived from structure-activity (receptor geometry independent) information.

Acetylcholinesterase↗
PubMed2004

Homology modeling and molecular dynamics study of GSK3/SHAGGY-like kinase.

Although the GSK3/SHAGGY-like kinase is a highly conserved serine/threonine kinase implicated in many signaling pathways in eukaryotes, the lack of knowledge of its three-dimensional (3D) structure has hindered efforts to understand the binding specificities of substrate and catalytic mechanism. To understand the structure-activity relationships, the protein 3D structure was built by using homology modeling based on the known X-ray diffraction structure of Glycogen synthase kinase-3beta (Gsk3beta) and the model structure was further refined using unrestrained molecular dynamics simulations. The research indicates that the general 3D organization of the GSK3/SHAGGY-like kinase is a typical kinase family and comprises an N-terminal domain of beta-sheet and a larger C-terminal domain mainly constituted by alpha-helix. In order to understand the molecular interactions between the natural substrate-ATP and GSK3/SHAGGY-like kinase, a 3D model of the complex ATP-GSK3/SHAGGY-like kinase is developed by molecular docking program, which is helpful to guide the experimental realization and the new mutant designs as well. One important finding is that the identification of the key binding-site residue of Lys69 which plays an important role in the catalysis of GSK3/SHAGGY-like kinase and this is in consistent with experimental observation.

Adenosine Triphosphate↗
PubMed2005

Incorporation of flexibility into rigid-body docking: applications in rounds 3-5 of CAPRI.

We have submitted models for all 9 targets in Rounds 3-5 of CAPRI and have predicted at least 30% of the correct contacts for 4 of the targets and at least 10% of the correct contacts for another 4 targets. We have employed a variety of techniques but have had the greatest success by combining established rigid-body docking with a variety of initial conformations generated by molecular dynamics.

Algorithms↗
PubMed2007

SR protein kinase 1 is resilient to inactivation.

SR protein kinase 1 (SRPK1) is a constitutively active kinase, which processively phosphorylates multiple serines within its substrates, ASF/SF2. We describe crystallographic, molecular dynamics, and biochemical results that shed light on how SRPK1 preserves its constitutive active conformation. Our structure reveals that unlike other known active kinase structures, the activation loop remains in an active state without any specific intraprotein interactions. Moreover, SRPK1 remains active despite extensive mutation to the activation segment. Molecular dynamics simulations reveal that SRPK1 partially absorbs the effect of mutations by forming compensatory interactions that maintain a catalytically competent chemical environment. Furthermore, SRPK1 is similarly resistant to deletion of its spacer loop region. Based upon a model of SRPK1 bound to a segment encompassing the docking motif and active-site peptide of ASF/SF2, we suggest a mechanism for processive phosphorylation and propose that the atypical resiliency we observed is critical for SRPK1's processive activity.

Crystallography, X-Ray↗
PubMed2006

Novel ketomethylene inhibitors of angiotensin I-converting enzyme (ACE): inhibition and molecular modelling.

Inhibition of angiotensin I-converting enzyme (ACE) has become an effective strategy in the treatment of hypertension and cardiovascular disease. Keto-ACE, a previously described C-domain selective ACE inhibitor, was used as the basis for the design, synthesis and molecular modelling of a series of novel ketomethylene derivatives for which ACE inhibition profiles and structural characterisation are reported. Ki determinations indicated that the introduction of a bulky aromatic tryptophan at the P2' position of keto-ACE significantly increased selectivity for the C-domain, while an aliphatic P2 Boc group conferred N-domain selectivity. These data were supported by the potential energies of the compounds docked with the C- and N-domains of ACE.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

New insights into the mechanism of protein-protein association.

Association of a protein complex follows a two-step mechanism, with the first step being the formation of an encounter complex that evolves into the final complex. Here, we analyze recent experimental data of the association of TEM1-beta-lactamase with BLIP using theoretical calculations and simulation. We show that the calculated Debye-Hückel energy of interaction for a pair of proteins during association resembles an energy funnel, with the final complex at the minima. All attraction is lost at inter-protein distances of 20 A, or rotation angles of >60 degrees from the orientation of the final complex. For faster-associating protein complexes, the energy funnel deepens and its volume increases. Mutations with the largest impact on association (hotspots for association) have the largest effect on the size and depth of the energy funnel. Analyzing existing evidence, we suggest that the transition state along the association pathway is the formation of the final complex from the encounter complex. Consequently, pairs of proteins forming an encounter complex will tend to dissociate more readily than to evolve into the final complex. Increasing directional diffusion by increasing favorable electrostatic attraction results in a faster forming and slower dissociating encounter complex. The possible applicability of electrostatic calculations for protein-protein docking is discussed.

Bacterial Proteins↗
PubMed1998

Rapid refinement of protein interfaces incorporating solvation: application to the docking problem.

A computationally tractable strategy has been developed to refine protein-protein interfaces that models the effects of side-chain conformational change, solvation and limited rigid-body movement of the subunits. The proteins are described at the atomic level by a multiple copy representation of side-chains modelled according to a rotamer library on a fixed peptide backbone. The surrounding solvent environment is described by "soft" sphere Langevin dipoles for water that interact with the protein via electrostatic, van der Waals and field-dependent hydrophobic terms. Energy refinement is based on a two-step process in which (1) a probability-based conformational matrix of the protein side-chains is refined iteratively by a mean field method. A side-chain interacts with the protein backbone and the probability-weighted average of the surrounding protein side-chains and solvent molecules. The resultant protein conformations then undergo (2) rigid-body energy minimization to relax the protein interface. Steps (1) and (2) are repeated until convergence of the interaction energy. The influence of refinement on side-chain conformation starting from unbound conformations found improvement in the RMSD of side-chains in the interface of protease-inhibitor complexes, and shows that the method leads to an improvement in interface geometry. In terms of discriminating between docked structures, the refinement was applied to two classes of protein-protein complex: five protease-protein inhibitor and four antibody-antigen complexes. A large number of putative docked complexes have already been generated for the test systems using our rigid-body docking program, FTDOCK. They include geometries that closely resemble the crystal complex, and therefore act as a test for the refinement procedure. In the protease-inhibitors, geometries that resemble the crystal complex are ranked in the top four solutions for four out of five systems when solvation is included in the energy function, against a background of between 26 and 364 complexes in the data set. The results for the antibody-antigen complexes are not as encouraging, with only two of the four systems showing discrimination. It would appear that these results reflect the somewhat different binding mechanism dominant in the two types of protein-protein complex. Binding in the protease-inhibitors appears to be "lock and key" in nature. The fixed backbone and mobile side-chain representation provide a good model for binding. Movements in the backbone geometry of antigens on binding represent an "induced-fit" and provides more of a challenge for the model. Given the limitations of the conformational sampling, the ability of the energy function to discriminate between native and non-native states is encouraging. Development of the approach to include greater conformational sampling could lead to a more general solution to the protein docking problem.

Animals↗
PubMed2005

A common pharmacophore for a diverse set of colchicine site inhibitors using a structure-based approach.

Modulating the structure and function of tubulin and microtubules is an important route to anticancer therapeutics, and therefore, small molecules that bind to tubulin and cause mitotic arrest are of immense interest. A large number of synthetic and natural compounds with diverse structures have been shown to bind at the colchicine site, one of the major binding sites on tubulin, and inhibit tubulin assembly. Using the recently determined X-ray structure of the tubulin:colchicinoid complex as the template, we employed docking studies to determine the binding modes of a set of structurally diverse colchicine site inhibitors. These binding models were subsequently used to construct a comprehensive, structure-based pharmacophore that in combination with molecular dynamics simulations confirms and extends our understanding of binding interactions at the colchicine site.

2-Methoxyestradiol↗
PubMed2006

On the use of orientational restraints and symmetry corrections in alchemical free energy calculations.

Alchemical free energy calculations are becoming a useful tool for calculating absolute binding free energies of small molecule ligands to proteins. Here, we find that the presence of multiple metastable ligand orientations can cause convergence problems when distance restraints alone are used. We demonstrate that the use of orientational restraints can greatly accelerate the convergence of these calculations. However, even with this acceleration, we find that sufficient sampling requires substantially longer simulations than are used in many published protocols. To further accelerate convergence, we introduce a new method of configuration space decomposition by orientation which reduces required simulation lengths by at least a factor of 5 in the cases examined. Our method is easily parallelizable, well suited for cases where a ligand cocrystal structure is not available, and can utilize initial orientations generated by docking packages.

Biophysics↗
PubMed2005

Geminate rebinding in R-state hemoglobin: kinetic and computational evidence for multiple hydrophobic pockets.

Biphasic geminate rebinding of CO to myoglobin upon flash photolysis has been associated to ligand distribution in hydrophobic cavities, structurally detected by time-resolved crystallography, xenon occupancy, and molecular simulations. We show that the time course of CO rebinding to human hemoglobin also exhibits a biphasic geminate rebinding when the protein is entrapped in wet nanoporous silica gel. A simple branched kinetic scheme, involving the bound state A, the primary docking site C, and a secondary binding site B was used to calculate the microscopic rates and the time-dependent population of the intermediate species. The activation enthalpies of the associated transitions were determined in the absence and presence of 80% glycerol. Potential hydrophobic docking cavities within the alpha and beta chains of hemoglobin were identified by computational modeling using xenon as a probe. A hydrophobic pocket on the distal side of the heme, corresponding to Xe4 in Mb, and a nearby site that does not have a correspondence in Mb were detected. Neither potential xenon sites on the proximal side nor a migration channel from the distal to proximal site was located. The small enthalpic barriers between states B and C are in very good agreement with the location of the xenon sites on the distal side. Furthermore, the connection between the two xenon sites is relatively open, explaining why the decreased mobility of the protein with viscosity only slightly perturbs the energetics of ligand migration between the two sites.

Binding Sites↗
PubMed1998

Surface solid angle-based site points for molecular docking.

We are developing a new site descriptor for the DOCK molecular modeling program suite. Sphgen, the current site description program for the DOCK suite, describes the pockets of a macromolecule by filling a volume with intersecting spheres. DOCK then identifies possible ligand orientations in the pocket by overlapping the atoms of proposed ligands with the sphere centers. Sphgen limits use of the DOCK program to concave binding regions, but macromolecular binding regions can be solvent-exposed rather than buried pockets. We present a more general site descriptor, based on the surface solid angle, which generates site points by determining the solid angle of exposure for points on the surface of the molecule, then identifying patches of surface with similar solid angle values which are then built into site points. We find possible ligand orientations by matching shape-based site points on the ligand and protein and demanding complementary solid angle values. Orientations are evaluated using the DOCK's force field-based score, which evaluates the Coulombic and van der Waals energy. The surface solid angle descriptor displays the complementary characteristics of the interfaces of our test systems: trypsin/trypsin inhibitor, chymotrypsin/turkey ovomucoid third domain, and subtilisin/chymotrypsin inhibitor. The solid angle site points can be used by DOCK to generate orientations within 1.5 A r.m.s.d. of the crystal structure orientation.

Algorithms↗
PubMed2004

Molecular simulation studies of a selenium-containing scFv catalytic antibody that mimics glutathione peroxidase.

GPX is a mammalian antioxidant selenoenzyme which protects biomembranes and other cellular components from oxidative damage by catalyzing the reduction of a variety of hydroperoxides (ROOH), using Glutathione (GSH) as the reducing substrate. The single-chain Fv fragment of the monoclonal antibody 2F3 (scFv2F3) can be converted into the selenium-containing Se-scFv2F3 by chemical modification of the serine. The new selenium-containing catalytic antibody Se-scFv2F3 acts as a glutathione peroxidase (GPX) mimic with high catalytic efficiency. In order to investigate which residue of scFv2F3 is converted into selenocysteine and to describe the proper reaction site of GSH to Se-scFv2F3, a three-dimensional structure of scFv2F3 is built by means of homology modeling. The 3D model is assessed by molecular dynamics (MD) simulation to determine its stability and by comparison with those of known protein structures. After the serine in the scFv2F3 is modified to selenocysteine, a catalytic antibody (abzyme) is obtained. From geometrical considerations, the solvent-accessible surface of the protein is examined. The computer-aided docking and energy minimization (EM) calculations of the abzyme-GSH complex are then carried out to explore the possible active site of the glutathione peroxidase mimic Se-scFv2F3. The structural information from the theoretically modeled complex can help us to further understand the catalytic mechanism of GPX.

Amino Acid Sequence↗
PubMed2006

Investigation of mechanism-based thrombin inhibitors: Implications of a highly conserved water molecule for the binding of coumarins within the S pocket.

The synthesis of novel coumarins bearing on the lateral side chain in the 3-position an amine or a guanidine group is described. In vitro evaluation highlighted 14d which possesses a meta aniline side chain as a very potent THR inhibitor. Surprisingly, the introduction of a guanidine moiety always led to a decrease in THR inhibiting properties. We, thus, used docking experiments to rationalize the SAR in the series. This study showed the crucial role of a conserved water molecule in the specificity pocket of THR during docking simulation in order to explain the inactivity of guanidine derivatives.

Antithrombins↗
PubMed2002

A structural model of the catalytic subunit-regulatory subunit dimeric complex of the cAMP-dependent protein kinase.

Previous neutron scattering studies elaborated the topographical relationship of the regulatory (R(IIalpha)) and catalytic (C(alpha)) subunits of the cAMP-dependent protein kinase. We present here the results of a set of computations that lead to an atomic model of the cAMP-dependent protein kinase heterodimer, Delta(1-91)R(IIalpha)-C(alpha). The first step in the modeling utilized the crystal structures for the porcine C(alpha) and bovine Delta(1-90)R(Ialpha) or rat Delta(1-111)R(IIbeta), to homology-model structures of the species and isoforms that had been used in the neutron scattering experiments (bovine C(alpha) subunit and murine Delta(1-91)R(IIalpha) subunit, respectively). A docking procedure, constrained by the dimensions and positions of the ellipsoids in the neutron-derived R-C model as well as mutagenesis data, was used to develop "best fit" models for the heterodimer. Simulated annealing, molecular dynamics, and energy minimization were then used to refine the side chain packing at the heterodimer interface. For comparison, the calculations were done using the homology models derived from both the R(Ialpha) and R(IIbeta) crystal structures. Both resultant models had many similarities. Each predicted similar interfaces. The R(Ialpha)-based model has 25% more hydrogen bonds than that based on R(IIbeta), with seven of these potential bonds in common. The distribution of hydrophobic, polar, and charged residues at the interface was similar for both models, with a distribution more characteristic of the exposed surface residues than those in the protein interior. The calculated interface area in each is relatively small (<2000 A(2)). The R(Ialpha)-based model, however, has a significantly better fit with the scattering data and is therefore the one of distinctly higher probability. With its small interface area that has a high proportion of charged and polar residues, the complex appears poised for dissociation, and each subunit existing as a stable entity. This result is consistent with the known physiological events required for cAMP-dependent activation of the kinase.

Amino Acid Sequence↗
PubMed1997

Computation of the binding of fully flexible peptides to proteins with flexible side chains.

Docking algorithms play an important role in the process of rational drug design and in understanding the mechanism of molecular recognition. An important determinant for successful docking is the extent to which the configurational space (including conformational changes) of the ligand/receptor system is searched. Here we describe a new, combinatorial method for flexible docking of peptides to proteins that allows full rotation around all single bonds of the peptide ligand and around those of a large set of receptor side chains. We have simulated the binding of several viral peptides to murine major histocompatibility complex class I H-2Kb. In addition, we have explored the limits of our method by simulating a complex between calmodulin and an 18-residue long helical peptide from calmodulin-dependent protein kinase IIalpha. The calculated peptide conformations generally matched well with the X-ray structures. Essential information about local flexibility and about residues that are responsible for strong binding was obtained. We have frequently observed considerable side-chain flexibility during the simulations, showing the need for a flexible treatment of the receptor. Our method may also be useful whenever the receptor side-chain conformation is not available or uncertain, as illustrated by the docking of an H-2Kb binding nonapeptide to the receptor structure taken from an octapeptide/H-2Kb complex.

Alanine↗