Showing papers on "Docking (molecular) published in 1999"

Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase

Abstract: MAP kinases phosphorylate specific groups of substrate proteins. Here we show that the amino acid sequence FXFP is an evolutionarily conserved docking site that mediates ERK MAP kinase binding to substrates in multiple protein families. FXFP and the D box, a different docking site, form a modular recognition system, as they can function independently or in combination. FXFP is specific for ERK, whereas the D box mediates binding to ERK and JNK MAP kinase, suggesting that the partially overlapping substrate specificities of ERK and JNK result from recognition of shared and unique docking sites. These findings enabled us to predict new ERK substrates and design peptide inhibitors of ERK that functioned in vitro and in vivo.

Consensus Scoring: A Method for Obtaining Improved Hit Rates from Docking Databases of Three-Dimensional Structures into Proteins

Abstract: We present the results of an extensive computational study in which we show that combining scoring functions in an intersection-based consensus approach results in an enhancement in the ability to discriminate between active and inactive enzyme inhibitors. This is illustrated in the context of docking collections of three-dimensional structures into three different enzymes of pharmaceutical interest: p38 MAP kinase, inosine monophosphate dehydrogenase, and HIV protease. An analysis of two different docking methods and thirteen scoring functions provides insights into which functions perform well, both singly and in combination. Our data shows that consensus scoring further provides a dramatic reduction in the number of false positives identified by individual scoring functions, thus leading to a significant enhancement in hit-rates.

Synthesis, CoMFA analysis, and receptor docking of 3,5-diacyl-2, 4-dialkylpyridine derivatives as selective A3 adenosine receptor antagonists.

Abstract: 3,5-Diacyl-2,4-dialkyl-6-phenylpyridine derivatives have been found to be selective antagonists at both human and rat A3 adenosine receptors (Li et al. J. Med. Chem. 1998, 41, 3186−3201). In the present study, ring-constrained, fluoro, hydroxy, and other derivatives in this series have been synthesized and tested for affinity at adenosine receptors in radioligand binding assays. Ki values at recombinant human and rat A3 adenosine receptors were determined using [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)-5‘-N-methylcarbamoyladenosine). Selectivity for A3 adenosine receptors was determined vs radioligand binding at rat brain A1 and A2A receptors, and structure−activity relationships at various positions of the pyridine ring (the 3- and 5-acyl substituents and the 2- and 4-alkyl substituents) were probed. At the 5-position inclusion of a β-fluoroethyl (7) or a γ-fluoropropyl ester (26) was favorable for human A3 receptor affinity, resulting in Ki values of 4.2 and 9.7 nM, respectively, while the pentafluoropro...

Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1.

Abstract: Recent X-ray crystallographic determination of the HIV-1 envelope glycoprotein gp41 core structure opened up a new avenue to discover antiviral agents for chemotherapy of HIV-1 infection and AIDS We have undertaken a systematic study to search for anti-HIV-1 lead compounds targeted to gp41 Using molecular docking techniques to screen a database of 20 000 organic molecules, we found 16 compounds with the best fit for docking into the hydrophobic cavity within the gp41 core and with maximum possible interactions with the target site Further testing of these compounds by an enzyme-linked immunosorbent assay and virus inhibition assays discerned two compounds (ADS-J1 and ADS-J2) having inhibitory activity at micromolar concentrations on the formation of the gp41 core structure and on HIV-1 infection These two compounds will be used as leads to design more effective HIV-1 inhibitors targeted to the HIV-1 gp41 core structure

A systematic study of low-resolution recognition in protein--protein complexes.

Abstract: A comprehensive nonredundant database of 475 cocrystallized protein-protein complexes was used to study low-resolution recognition, which was reported in earlier docking experiments with a small number of proteins. The docking program GRAMM was used to delete the atom-size structural details and systematically dock the resulting molecular images. The results reveal the existence of the low-resolution recognition in 52% of all complexes in the database and in 76% of the 113 complexes with an interface area >4,000 A(2). Limitations of the docking and analysis tools used in this study suggest that the actual number of complexes with the low-resolution recognition is higher. However, the results already prove the existence of the low-resolution recognition on a broad scale.

MCDOCK: a Monte Carlo simulation approach to the molecular docking problem.

Abstract: Prediction of the binding mode of a ligand (a drug molecule) to its macromolecular receptor, or molecular docking, is an important problem in rational drug design We have developed a new docking method in which a non-conventional Monte Carlo (MC) simulation technique is employed A computer program, MCDOCK, was developed to carry out the molecular docking operation automatically The current version of the MCDOCK program (version 10) allows for the full flexibility of ligands in the docking calculations The scoring function used in MCDOCK is the sum of the interaction energy between the ligand and its receptor, and the conformational energy of the ligand To validate the MCDOCK method, 19 small ligands, the binding modes of which had been determined experimentally using X-ray diffraction, were docked into their receptor binding sites To produce statistically significant results, 20 MCDOCK runs were performed for each protein–ligand complex It was found that a significant percentage of these MCDOCK runs converge to the experimentally observed binding mode The root-mean-square (rms) of all non-hydrogen atoms of the ligand between the predicted and experimental binding modes ranges from 025 to 184 A for these 19 cases The computational time for each run on an SGI Indigo2/R10000 varies from less than 1 min to 15 min, depending upon the size and the flexibility of the ligands Thus MCDOCK may be used to predict the precise binding mode of ligands in lead optimization and to discover novel lead compounds through structure-based database searching

Examination of shape complementarity in docking of Unbound proteins

Abstract: Here we carry out an examination of shape complementarity as a criterion in protein- protein docking and binding. Specifically, we examine the quality of shape complementarity as a critical determinant not only in the docking of 26 protein-protein ''bound'' complexed cases, but in particular, of 19 ''unbound'' protein-protein cases, where the structures have been determined sepa- rately. In all cases, entire molecular surfaces are utilized in the docking, with no consideration of the location of the active site, or of particular residues/ atoms in either the receptor or the ligand that participate in the binding. To evaluate the goodness of the strictly geometry-based shape complementar- ity in the docking process as compared to the main favorable and unfavorable energy components, we study systematically a potential correlation be- tween each of these components and the root mean square deviation (RMSD) of the ''unbound'' protein-protein cases. Specifically, we examine the non-polar buried surface area, polar buried sur- face area, buried surface area relating to groups bearing unsatisfied buried charges, and the number of hydrogen bonds in all docked protein-protein interfaces. For these cases, where the two proteins have been crystallized separately, and where entire molecular surfaces are considered without a predefi- nition of the binding site, no correlation is observed. None of these parameters appears to consistently improve on shape complementarity in the docking of unbound molecules. These findings argue that simplicity in the docking process, utilizing geo- metrical shape criteria may capture many of the essential features in protein-protein docking. In particular, they further reinforce the long held no- tion of the importance of molecular surface shape complementarity in the binding, and hence in dock- ing. This is particularly interesting in light of the fact that the structures of the docked pairs have been determined separately, allowing side chains on the surface of the proteins to move relatively freely.

The sensitivity of the results of molecular docking to induced fit effects: application to thrombin, thermolysin and neuraminidase.

Abstract: This paper describes the application of PRO_LEADS to the flexible docking of ligands into crystallographically derived enzyme structures that are assumed to be rigid. PRO_LEADS uses a Tabu search methodology to perform the flexible search and an empirically derived estimate of the binding affinity to drive the docking process. The paper tests the extent to which the assumption of a rigid enzyme compromises the accuracy of the results. All-pairs docking experiments are performed for three enzymes (thrombin, thermolysin and influenza virus neuraminidase) based on six or more ligand-enzyme crystal structures for each enzyme. In 76% of the cases, PRO_LEADS can successfully identify the correct ligand conformation as the lowest energy configuration when the enzyme structure is derived from that ligand's crystal structure, but the methodology only docks 49% of the cases successfully when the ligand is docked against enzyme crystal structures derived from other ligands. Small movements in the enzyme structure lead to an under-prediction in the energy of the correct binding mode by up to 14 kJ/mol and in some cases this under-prediction can lead to the native mode not being recognised as the lowest energy solution. The type of movements responsible for mis-docking are: the movement of sidechains as a result of changes in C alpha position; the movement of sidechains without changes in C alpha position; the movement of flexible portions of main chains to facilitate the formation of hydrogen bonds; and the movement of metal atoms bound to the enzyme active site. The work illustrates that the assumption of a rigid active site can lead to errors in identification of the correct binding mode and the assessment of binding affinity, even for enzymes which show relatively small shift in atomic positions from one ligand to the next. A good docking code, such as PRO_LEADS, can usually dock successfully if there is induced fit in relatively rigid enzymes but there remains the need to develop improved strategies for dealing with enzyme flexibility. The work implies that treatments of enzyme flexibility which focus only on sidechain rotations will not deal with the critical shifts responsible for mis-docking of ligands in thrombin, thermolysin and neuraminidase. The paper demonstrates the utility of all pairs docking experiments as a method of assessing the effectiveness of docking methodologies in dealing with enzyme flexibility.

Flexible ligand docking: a multistep strategy approach.

Abstract: A flexible ligand docking protocol based on a divide-and-conquer strategy is investigated. This approach first separates total search space into conformation and orientation space. It uses a grid-based method to sample the conformation of an unbound ligand and to select the low-energy conformers. Rigid docking is then carried out to locate the low-energy binding orientations for these conformers. These docking structures are subsequently subjected to structure refinement including molecular mechanics minimization, conformational scanning at the binding site and a short period of molecular dynamics-based simulated annealing. This approach has been applied to twelve ligand-protein complexes with three to sixteen rotatable bonds. The docked lowest-energy structures have root mean square deviations ranging from 0.64 A to 2.01 A with respect to the corresponding crystal structures. The effect of atomic charges and van der Waals parameters on the docking results, and the role of the dielectric constant in the conformation sampling are discussed in detail. A fragment-based docking approach that takes advantages of the divide-and-conquer strategy has also been explored and the results are compared with those produced by a whole molecule-based approach.

Exhaustive docking of molecular fragments with electrostatic solvation.

Abstract: A new method is presented for docking molecular fragments to a rigid protein with evaluation of the binding energy. Polar fragments are docked with at least one hydrogen bond with the protein while apolar fragments are positioned in the hydrophobic pockets. The electrostatic contribution to the binding energy, which consists of screened intermolecular energy and protein and fragment desolvation terms, is evaluated efficiently by a numerical approach based on the continuum dielectric approximation. The latter is also used to predetermine the hydrophobic pockets of the protein by rolling a low dielectric sphere over the protein surface and calculating the electrostatic desolvation of the protein and van der Waals interaction energy. The method was implemented in the program SEED (solvation energy for exhaustive docking). The SEED continuum electrostatic approach has been successfully validated by a comparison with finite difference solutions of the Poisson equation for more than 2,500 complexes of small molecules with thrombin and the monomer of HIV-1 aspartic proteinase. The fragments docked by SEED in the active site of thrombin reproduce the structural features of the interaction patterns between known inhibitors and thrombin. Moreover, the combinatorial connection of these fragments yields a number of compounds that are very similar to potent inhibitors of thrombin. Proteins 1999;37:88-105.

Docking of cationic antibiotics to negatively charged pockets in RNA folds.

Abstract: The binding of aminoglycosides to RNA provides a paradigm system for the analysis of RNA-drug interactions. The electrostatic field around three-dimensional RNA folds creates localized and defined negatively charged regions which are potential docking sites for the cationic ammonium groups of aminoglycosides. To explore in RNA folds the electronegative pockets suitable for aminoglycoside binding, we used calculations of the electrostatic field and Brownian dynamics simulations of cation diffusion. We applied the technique on those RNA molecules experimentally known to bind aminoglycosides, namely, two tobramycin aptamers (Wang, Y.; Rando, R. R. Chem. Biol. 1995, 2, 281-290): the aminoglycoside-binding region in 16S ribosomal RNA (Moazed, S.; Noller, H. F. Nature 1987, 327, 389-394) and the TAR RNA from human immunodeficiency virus (Mei, H.-Y.; et al. Bioorg. Med. Chem. Lett. 1995, 5, 2755-2760). For the aptamers and ribosomal RNA, for which the binding sites of the aminoglycosides are known, a good agreement between negatively charged pockets and the binding positions of the drugs was found. On the basis of variations between neomycin-like and kanamycin-like aminoglycosides in the interaction with the electrostatic field of ribosomal RNA, we propose a model for the different binding specificities of these two classes of drugs. The spatial congruence between the electronegative pockets in RNA folds and binding positions of aminoglycosides was used to dock aminoglycosides to ribosomal and TAR RNAs. Molecular dynamics simulations were used to analyze possible RNA-drug interactions. Aminoglycosides inhibit the binding of the viral Tat protein to TAR RNA; however, the drug-binding sites are still unknown. Thus, our docking approach provides first structural models for TAR-aminoglycoside complexes. The RNA-drug interactions observed in the modeled complexes support the view that the antibiotics might lock TAR in a conformation with low affinity for the Tat protein, explaining the experimentally found aminoglycoside inhibition of the Tat-TAR interaction (Mei, H.-Y.; et al. Bioorg. Med. Chem. Lett. 1995, 5, 2755-2760).

Evaluation of PMF scoring in docking weak ligands to the FK506 binding protein

Abstract: A new knowledge-based scoring function (PMF-score), implemented into the DOCK4 program, was used to screen a database of 3247 small molecules for binding to the FK506 binding protein (FKBP). The computational ranking of these compounds was compared to the binding affinities measured by NMR. It was demonstrated that small, weakly binding molecules have, on average, higher computational scores than nonbinders and are enriched in the upper ranks of the computational scoring lists. In addition, the results obtained with the PMF scoring function were superior (by 30-120% larger enrichment factors) to those obtained with the standard force field score of DOCK4. The reliable ranking of small, weakly binding molecules offers new ways of designing building blocks in combinatorial libraries as well as SAR by NMR libraries with the increased chance of identifying suitable lead compounds for drug design.

The Difference between the CB1 and CB2Cannabinoid Receptors at Position 5.46 Is Crucial for the Selectivity of WIN55212-2 for CB2

Abstract: It has been reported that WIN55212-2, a prototypic aminoalkylindole, has higher affinity for CB2 than for CB1. To explain the selectivity of WIN55212-2 for CB2, molecular modeling studies were performed to probe the interacting sites between WIN55212-2 and cannabinoid receptors. In TMH5 the position 5.46 is a Phe in CB2 versus a Val in CB1. Docking of WIN55212-2 into the models of CB1 and CB2predicts that F5.46 will result in a greater aromatic stacking of CB2 with WIN55212-2. Using site-directed mutagenesis, this hypothesis was tested by exchanging the amino acids at position 5.46 between CB1 and CB2. Two mutations, including a Phe to Val mutation at the position 5.46 in CB2(CB2F5.46V), and a corresponding Val to Phe mutation at the position 5.46 in CB1 (CB1V5.46F), were made. The mutant receptors were transfected into 293 cells, and stable cell lines expressing similar numbers of receptors as wild-type receptors were chosen for additional ligand binding and cAMP accumulation studies. In ligand- binding assays, the CB2F5.46V mutation decreased the affinity of WIN55212-2 for CB2 by 14-fold. In contrast, the CB1V5.46F mutation increased the affinity of WIN55212-2 for CB1 by 12-fold. However, these mutations did not change the affinity of HU-210, CP-55940, and anandamide for CB1and CB2. In cAMP accumulation assays, the changes in EC50 values of WIN55212-2 were consistent with the changes in its binding affinity caused by the mutations. These results strongly support the hypothesis that the selectivity of WIN55212-2 for CB2 over CB1 is attributable to the change from Val in CB1 at position 5.46 to Phe in CB2.

Homology modeling of gelatinase catalytic domains and docking simulations of novel sulfonamide inhibitors.

Abstract: Three-dimensional models for the catalytic domain of gelatinases (MMP-9 and -2) have been constructed based on the X-ray crystal structure of MMP-3. Conformations of the loop segment which forms the bottom half of the S1‘ subsite but shows conformational diversity among the crystal structures of other MMPs have been explored by simulated annealing of each gelatinase model complexed with two highly potent “probe” inhibitors. Representative catalytic domain models have been selected for each gelatinase from the set of generated conformations based on shape complementarity of the loop to the probe inhibitors. The single model selected for MMP-9 was utilized to explain the structure−activity relationship of our novel sulfonamide inhibitors. Molecular dynamics (MD) simulations of the complex models revealed important features of the binding mechanism of our inhibitors: (i) the ligand carboxylate group coordinating to the catalytic zinc ion and hydrogen bonding to the Glu219 side chain, (ii) one of the sulfony...

Docking of Glycosaminoglycans to Heparin-Binding Proteins: Validation for aFGF, bFGF, and Antithrombin and Application to IL-8

Abstract: Heparin−protein interactions play an important role in many steps of the immune system. Here, we evaluated the search capabilities of three widely used programsGRID, DOCK, and AutoDockfor heparin binding sites. Because of the weak surface complementarity and the high charge density of the sulfated sugar chain, the docking of heparin to its protein partners presents a challenging task for computational docking. Our protocols were tested on antithrombin and acidic and basic fibroblast growth factor, the only three proteins for which structures of their complexes with heparin are available. With all three programs, the heparin binding site for these test cases was determined correctly. We then used these protocols to predict the heparin binding site on Interleukin-8, a chemokine with a central role in the human immune response. The results indicate that His18, Lys20, Arg60, Lys64, and Arg68 in interleukin-8 bind to heparin.

Combinatorial docking and combinatorial chemistry: design of potent non-peptide thrombin inhibitors.

Abstract: A computational algorithm was used to design automatically novel thrombin inhibitors that are available from a single-step chemical reaction. The compounds do not contain amide bonds, are achiral and have a molecular weight below 400. Of the 10 compounds that were synthesized, five bind to thrombin with a Ki in the nanomolar range. Subsequent X-ray structure determination of the thrombin-inhibitor complex for the best compound (Ki=95 nM) confirms the predicted binding mode. The novel algorithm is applicable to a broad range of chemical reactions.

Two-stage method for protein-ligand docking.

Abstract: A two-stage method for the computational prediction of the structure of protein-ligand complexes is proposed. Given an experimentally determined structure of the protein, in the first stage a large number of plausible ligand conformations is generated using the fast docking algorithm FlexX. In the second stage these conformations are minimized and reranked using a method based on a classical force field. The two-stage method is tested for 10 different protein-ligand complexes. For 9 of them experimentally determined structures are known. It turns out that the two-stage method strongly improves the predictive power as compared to that of the fast docking stage alone. The tenth case is a bona fide prediction of a complex of thrombin with a new inhibitor for which no experimentally determined structure is available so far.

Quantitative structure-activity relationship of human neutrophil collagenase (MMP-8) inhibitors using comparative molecular field analysis and X-ray structure analysis.

Abstract: A set of 90 novel 2-(arylsulfonyl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxylates and -hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil collagenase (MMP-8) was designed, synthesized, and investigated by 3D-QSAR techniques (CoMFA, CoMSIA) and X-ray structure analysis. Docking studies of a reference compound are based on crystal structures of MMP-8 complexed with peptidic inhibitors to propose a model of its bioactive conformation. This model was validated by a 1. 7 A X-ray structure of the catalytic domain of MMP-8. The 3D-QSAR models based on a superposition rule derived from these docking studies were validated using conventional and cross-validated r2 values using the leave-one-out method, repeated analyses using two randomly chosen cross-validation groups plus randomization of biological activities. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which were found to correspond to experimentally determined MMP-8 catalytic site topology in terms of steric, electrostatic, and hydrophobic complementarity. Subsets selected as smaller training sets using 2D fingerprints and maximum dissimilarity methods resulted in 3D-QSAR models with remarkable correlation coefficients and a high predictive power. This allowed to compensate the weaker zinc binding properties of carboxylates by introducing optimal fitting P1' residues. The final QSAR information agrees with all experimental data for the binding topology and thus provides clear guidelines and accurate activity predictions for novel MMP-8 inhibitors.

The identification of three biologically relevant globotriaosyl ceramide receptor binding sites on the Verotoxin 1 B subunit.

Abstract: The Verotoxin 1 (VT1) B subunit binds to the glycosphingolipid receptor globotriaosylceramide (Gb3). Receptor-binding specificity is associated with the terminally linked Galα(1–4) Galβ disaccharide sequence of the receptor. Recently, three globotriose (Galα[1–4] Galβ [1–4] Glcβ) binding sites per B-subunit monomer were identified by crystallography. Two of these sites (sites I and II) are located adjacent to phenylalanine-30. Site I was originally predicted as a potential Gb3 binding site on the basis of sequence conservation, and site II was additionally predicted based on computer modelling and receptor docking. The third (site III) was also identified by crystallography and is located at the N-terminal end of the α-helix. To determine the biological significance of sites II and III, and to support our previous findings of the significance of site I, we examined the binding properties and cytotoxicity of VT1 mutants designed to block Gb3 binding at each site selectively. The Scatchard analysis of saturation-binding data for each mutant revealed that only the amino acid substitutions predicted to affect site I (D-17E) or site II (G-62T) caused reductions in the binding affinity and capacity of VT1 for Gb3. Similarly, those mutations at sites I and II also caused significant reductions in both Vero and MRC-5 cell cytotoxicity (by seven and five logs, respectively, for G-62T and by four and two logs, respectively, for D-17E). In contrast, the substitution of alanine for W-34 at site III did not reduce the high-affinity binding of the B subunit, despite causing a fourfold reduction in the receptor-binding capacity. The corresponding mutant W-34A holotoxin had a two-log reduction in cytotoxicity on Vero cells and no statistically significant reduction on MRC-5 cells. We conclude that the high-affinity receptor binding most relevant for cell cytotoxicity occurs at sites I and II. In contrast, site III appears to mediate the recognition of additional Gb3 receptor epitopes but with lower affinity. Our results support the significance of the indole ring of W-34 for binding at this site.

The role of waters in docking strategies with incremental flexibility for carbohydrate derivatives: heat-labile enterotoxin, a multivalent test case.

Abstract: Molecular docking studies of carbohydrate derivatives in protein binding sites are often challenging because of water-mediated interactions and the inherent flexibility of the many terminal hydroxyl groups. Using the recognition process between heat-labile enterotoxin from Escherichia coli and ganglioside GM1 as a paradigm, we developed a modeling protocol that includes incremental conformational flexibility of the ligand and predicted water interactions. The strategy employs a modified version of the Monte Carlo docking program AUTODOCK and water affinity potentials calculated with GRID. After calibration of the protocol on the basis of the known binding modes of galactose and lactose to the toxin, blind predictions were made for the binding modes of four galactose derivatives: lactulose, melibionic acid, thiodigalactoside, and m-nitrophenyl-alpha-galactoside. Subsequent crystal structure determinations have demonstrated that our docking strategy can predict the correct binding modes of carbohydrate derivatives within 1.0 A from experiment. In addition, it is shown that repeating the docking simulations in each of the seemingly identical binding sites of the multivalent toxin increases the chance of finding the correct binding mode.

Structure and function of a membrane-bound murine MHC class I molecule

Abstract: MHC molecules are expressed at the surface of nucleated cells to present peptides to T cells. Structural information on MHC molecules has been gathered by x-ray crystallography techniques by using soluble proteins. Although relationships between MHC molecules and cell membranes have not been studied in detail, they are of critical importance for T cell recognition. Using a chemically modified lipid, we have been able to capture and orient histidine-tagged MHC molecules on lipid membranes. Surface plasmon resonance experiments show that the protein binds to the nickel lipid in a specific manner and in an oriented fashion, which allows T cell receptor binding. Similar lipid surfaces have been used to grow two-dimensional crystals and to determine the structure of a membrane-anchored murine H-2Kb MHC class I molecule. The docking of the crystallographic structure into the three-dimensional reconstructed structure derived from the two-dimensional crystals allows us to determine that the histidine tag is near the membrane surface and that the MHC molecule is in an upright position, exposing the peptide/alpha1-alpha2 domains toward the T cell.

VRDD: applying virtual reality visualization to protein docking and design.

Abstract: We have developed an interactive docking program called VRDD. It offers various modes of displaying molecules in an immersive, three-dimensional virtual reality (VR) environment. It allows a user to interactively perform molecular docking aided by automatic docking and side chain conformational search. Binding free energies are computed in real time, and the program enables the user to explore only clash-free orientations of a ligand. VRDD also supplies visual and auditory feedback during docking and side chain search, indicating the levels of atomic overlap and interaction energy. The stunning VR graphics immerse users in the scene and can maximally stimulate their design intuition. We have tested VRDD on three cases with increasing complexity: a nine-residue-long peptide bound to a major histocompatibility complex (MHC) molecule, barstar bound to barnase, and an antibody bound to a hemagglutinin. Without prior knowledge, combinations of hand-docking and automatic refinement led to accurate complex structures for the first two complexes. The third case, for which all automatic docking algorithms failed to identify the correct complex in a previous blind test, also failed for VRDD. Our results show that the combination of VR docking and automatic docking can make unique contributions to molecular modeling.