What if I have a question that is not answered here or in the manual? Installation Questions. How is dms installed? Should AMBERHOME be. This tutorial introduces DOCK Score in DOCK6 and describes the preparation of input Please see the DOCK6 manual for futher details. If you have installed DOCK6, this script can be found in the bin directory. . To select other options, please read the DOCK 6 Manual.
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This manuscript presents the latest algorithmic and methodological developments to the structure-based design program DOCK 6. An important strategy during development involved use of three orthogonal metrics for assessment and validation: Relative to earlier versions, a key outcome of the work is a significant increase in pose reproduction success in going from DOCK 4. Companion cross-docking and enrichment studies with the new version highlight other strengths and remaining areas for improvement, especially for systems containing metal ions.
DOCK 6: Impact of New Features and Current Docking Performance
The source code for DOCK 6. The current performance of DOCK version 6. The effectiveness of DOCK is demonstrated in pose reproduction, cross-docking picturedand enrichment experiments to systems that are of interest as drug targets.
The current release is available for download at: Computer-based molecular docking can facilitate the early stages of drug discovery through systematic pre-screening of ligands i. At its first inception, DOCK version 1 DOCK 1was fundamentally a geometric shape-matching algorithm [ 4 ] that evaluated the quality of ligand-receptor complexes on steric overlap.
Importantly, the DOCK 3 branch is still actively developed, and it is one of the most rigorously validated molecular docking programs in terms of correspondence between predictions and high-throughput screening or X-ray crystallographic experiments. The molecular docking approach has precipitated a number of compounds with experimental activity; a thorough, but not comprehensive, list of successes over the past five years was recently compiled by Coleman et al.
In addition to direct empirical confirmation, the performances of DOCK and other docking programs are occasionally evaluated in formal docking competitions and special symposia. Contributing to the success of DOCK is the open-source codebase free for registered academic users and the active community of developers and users over the past three decades. One of the core features that distinguishes DOCK 6 from other docking programs is the anchor-and-grow search algorithm Figure 1[ 12 ] a breadth-first method for small molecule conformational sampling.
In brief, a candidate ligand is disassembled into rigid segments connected by rotatable bonds RBfor example see Figure 1a, b. A number of the largest segments, termed here the anchors labeled A1 and A2 in Figure 1are oriented to the binding site using binding site spheres and a graph-matching algorithm.
As each ligand segment is grown, conformers are energy minimized and pruned before proceeding to the next step Figure 1e. Circles represent partially or fully grown ligand conformers, which are energy minimized and pruned following each addition of a segment S 1S 2… S N.
The purpose of this manuscript is to introduce and discuss several important updates to the DOCK 6 codebase, focused on version 6.
First, in Methods and Detailswe present the SB test set — an expanded version of the SB test set [ 47 ] — that incorporates crystallographic receptor-ligand complexes for large-scale validation and testing of algorithmic developments.
Further, we discuss the protocols and input file parameters recommended for using DOCK in either a pose reproduction or virtual screening enrichment capacity. Impact of New Featureswe discuss in detail new features including: Other new features, including a footprint similarity scoring function, a symmetry-corrected RMSD algorithm, a database filter, and docking forensic tools are briefly summarized, then described in more detail in Supporting Information.
Current Docking Performancewe discuss the latest performance of the program DOCK in terms of pose reproduction, cross-docking, and enrichment.
DOCK tutorial with Streptavidin – Rizzo_Lab
In addition, we assess the performance of DOCK relative to previous versions. Overall, these works represent as yet unreported novel docking results, obtained mxnual newly added DOCK functionality, over a significantly large validation test set systems. Three key outcomes from this work include: The dovk6 major advance in the docking algorithm described in this work was not due to any one change, but rather a series of complimentary and independent incremental improvements that employed a range of orthogonal test sets and tools.
The SB test set of crystallographic receptor-ligand complexes described in Mukherjee et al. Receptor and ligand preparation protocols were updated, and a considerable number of new systems were introduced. New entries include 72 additional systems from the Astex diverse set, [ 37 ] 29 additional systems from the Directory of Useful Decoys [ 48 ] DUD, discussed in Brozell et al.
From the original SB test set, five systems with semi-covalent boron-containing ligands and two other aberrant systems were removed. A thorough description of the test set preparation protocols can be found in the original SB paper.
Beginning with SB, protocols were revised for compatibility with Amber 11, [ 50 ] and to support systems with small-molecule cofactors. In SB, ligands were protonated and initially dovk6 empirical Gasteiger-Marsili mxnual [ 51 ] with the program MOE, [ 44 ] taking every manua to match the protonation state and net charge described in the literature for the crystallographic complex. Small-molecule cofactors, when present, follow the same preparation protocols as the ligands. Receptors were protonated and assigned ff99SB parameters [ 54 ] in tLEaP AmberToolsthen subjected to short energy minimizations with heavy restraints on non-hydrogen atoms using sander Amber Importantly, the new protocols enable the energy minimization of newly-added receptor hydrogen atoms in the presence of the bound cognate ligand and cofactor, if applicableallowing for physically reasonable positioning.
In addition, the new top2mol2 tool allows for facile conversion between Amber parm and crd files and separate receptor, ligand, and cofactor mol2 files Tripos Sybyl conventions [ 55 ] while retaining the atomic partial charges, bond types, and atom types as assigned by tLEaP receptor or antechamber ligand, cofactors.
The first key experiment, pose reproduction, involves taking a known i. The test is a docking success if the top-scoring pose is within 2.
Across a large test set, e. Here, we briefly present methods for preparing the system and performing pose reproduction experiments in the program DOCK, including input file parameters, which together are the generally recommended protocols for this type of experiment.
2012 DOCK tutorial with Streptavidin
Standard pose reproduction experiment following a flexible docking protocol. First, the molecular surface of the receptor absent hydrogen atoms and the ligand was determined using the DMS program [ 57 ] with a probe radius of 1. Then, the DOCK accessory program s phgen [ 4 ] was used to generate spheres within dpck6 ligand binding site. A maximum of 75 spheres that were within 8.
Following sphere generation, the DOCK accessory program showbox was used to construct a box around the spheres plus an 8. This resulting grid formed the basis for computing single grid energy SGE score, which was used in all tests in this manuscript unless otherwise noted. For pose reproduction experiments, the ligands were treated as flexible based on manuwl the FLX protocol in Mukherjee et al.
Although a complete example input file is distributed with the test set, some of the important parameters are as follows: During ligand growth, a repulsive van der Waals term with an exponent of 12 referred to as the repulsive-only internal energy was used to alleviate internal clashes.
A simplex minimizer [ dovk6 ] was employed for one cycle manuaal minimization per ligand conformation per stage of growth, and the score was considered to be converged if the changes in energy between steps were less than 0. The translational, doc6, and torsional step sizes for the simplex minimizer were 1. Any conformer with a score greater than Finally, a maximum number of scored conformers were retained for examination, following best-first clustering with a 2.
The second key experiment, cross-docking, is an additional method for evaluating the pose reproduction ability of docking programs under different conditions. Here, multiple receptor-ligand crystallographic complexes are aligned into a common reference frame. As part of the SB release, 24 cross-docking families were prepared ranging from 6 to 59 systems per family and made available for download.
Doc,6 receptors in each family were aligned on the alpha carbon atoms using the matchmaker tool in the Chimera program. In addition, systems with ligands that bound in a disparate binding site were removed. For some particular families, however, models with larger-than-expected backbone Odck6 were deliberately retained for biological motives.
As an example, active and inactive conformations of EGFR were retained in the same family. Finally, each group was visually inspected to further ensure that all structures were well aligned. An important assumption in cross-docking is that the aligned ligand pose in each receptor provides a physically reasonable RMSD reference for dok6 success or failure of off-diagonal elements.
However, some aligned ligand poses may not fit in a non-native binding site due to, for example, induced fit effects or receptor mutations, and thus should not be used as a docking reference. If the RMSD of the minimized crystallographic ligand exceeded 2. Stated another way, if any particular crystallographic ligand pose was incompatible with an off-diagonal receptor, that pair was not considered when computing docking statistics.
A particularly useful way to evaluate cross-docking performance is to employ heatmapsas illustrated for a mxnual family in Figure 3. Here, ligands are labeled along the y -axis, and receptors are labeled in the same order along the x -axis. The diagonal of the matrix, or those cells representing the cognate native receptor-ligand pairs, is marked with white dots. Cells in the matrix are color-coded using the docking outcome definitions previously described for pose reproduction experiments: Ligand order along the y-axis is determined lexicographically first by success rate number of blue squaresthen by scoring manua, number of green squaresthen by sampling failures number of red squaresand finally by the number of non-viable pairings number of gray squares.
The overall matrix docking success is computed by dividing the number of docking successes blue squares by the number of viable docking calculations N 2 minus the number of gray squares. Similar calculations can be made to determine the matrix scoring failure rate green squaresthe matrix sampling failure rate red squaresor the success and failure rates pertaining to the diagonal. The diagonal is marked with white dots. In this matrix, there are total squares: It is important to emphasize that the protocol decisions defined here for crossdocking and elsewhere in the manuscript are an informed design choice, and we recognize that other researchers may have different ways of approaching system preparation and docking protocols.
Stated another way, some structures when overlaid produce un-physical complexes and the standard 2. On-the-fly docking protocols that includes both receptor and ligand flexibility in DOCK are under investigation. For the present study, however, receptor flexibility tests nanual not presented. The third key experiment, enrichment, provides a means to assess the performance of DOCK in a virtual screening capacity see Eock6 4.
Enrichment involves rank-ordering a database of compounds containing a set of known actives seeded among a large number of decoys according to their predicted binding affinity to a target. Ideally, known actives are ranked higher than the decoys by the docking program or method used.
One common metric for evaluating the outcome of an enrichment experiment is to use receiver operating characteristic ROC curves. These curves plot the true positive rate true positives divided by the total number of positives, also called sensitivity against the false positive rate false positives divided by the total number of decoys, mwnual described as [1-specificity] for a rank-ordered list.
Good early enrichment is considered to be important for virtual screening where only a small number of compounds might be purchased for experimental testing. Enrichment studies using an earlier version of DOCK version 6. Schematic protocol for enrichment experiment.
In this specific example, five actives represented by black circles and ten decoys represented by open circles are shown. Here, two different outcomes are described: In the initial DOCK preparation steps, the receptor is treated the same as in the pose reproduction experiments. It is necessary to note that, in some cases, different compilers, environments, or computer architectures can influence docking speed.
Thus, while useful as a general guide, timings presented in this manuscript are highly specific to our infrastructure and should be viewed in that light. The most recent version of DOCK is available to registered users online at http: In addition, the SB test set, including example input file parameters, is available for download at www.
Previous versions of DOCK 5. To alleviate potential internal clashes among ligand atoms during torsional sampling, users could specify an optional clash overlap function.