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<!DOCTYPE HTML PUBLIC "-//W3C//DTD HTML EXPERIMENTAL 970324//EN"><HTML><HEAD><META NAME="GENERATOR" CONTENT="Adobe FrameMaker 5.5/HTML Export Filter"><LINK REL="STYLESHEET" HREF="Manual.css"><TITLE> Overview of the DOCK program suite</TITLE></HEAD><BODY BGCOLOR="#ffffff"><H3 CLASS="Heading-3"><A NAME="pgfId=2762"> </A>Overview of the DOCK program suite</H3><P CLASS="Normal"><A NAME="pgfId=2763"> </A>C.M. Oshiro</P><DIV><H4 CLASS="Heading-4"><A NAME="pgfId=2708"> </A>Programs</H4><P CLASS="Body"><A NAME="pgfId=2764"> </A>The relationship between the main programs in the dock suite is depicted in <A HREF="Manual.4.html#30086" CLASS="XRef">Figure 1.</A> These routines will be described below; more details can be found in various papers. We list a small subset of papers. Review articles on the method can be found in Kuntz [<A HREF="Manual.4.html#36942" CLASS="XRef">1</A>] and Kuntz, Meng and Shoichet [<A HREF="Manual.4.html#39569" CLASS="XRef">2</A>].</P><DIV><H5 CLASS="Figure"><A NAME="pgfId=2757"> </A>Figure 1. <A NAME="30086"> </A>Main programs in DOCK suite</H5><DIV><MAP NAME="Manual-1"></MAP><IMG SRC="Manual-1.gif" USEMAP="#Manual-1"></DIV><P CLASS="Body"><A NAME="pgfId=2986"> </A>Program <A NAME="marker=2789"> </A><A HREF="Manual.20.html#17338" CLASS="XRef">sphgen</A> identifies the active site, and other sites of interest, and generates the sphere centers which fill the site. It has been described in the original paper: Kuntz, et al. [<A HREF="Manual.4.html#15734" CLASS="XRef">3</A>]. Program <A NAME="marker=2794"> </A><A HREF="Manual.1b.html#37839" CLASS="XRef">grid</A> generates the scoring grids; details can be found in Shoichet, Bodian and Kuntz [<A HREF="Manual.4.html#21226" CLASS="XRef">4</A>] and Meng, Shoichet and Kuntz [<A HREF="Manual.4.html#27781" CLASS="XRef">5</A>]. Within the dock suite of programs, the program dock matches spheres (generated by <A HREF="Manual.20.html#17338" CLASS="XRef">sphgen</A>) with ligand atoms and uses scoring grids (from <A NAME="marker=2801"> </A><A HREF="Manual.1b.html#37839" CLASS="XRef">grid</A>) to evaluate ligand orientations; descriptions can be found in Kuntz, et al. [<A HREF="Manual.4.html#15734" CLASS="XRef">3</A>] and Shoichet, Bodian and Kuntz [<A HREF="Manual.4.html#21226" CLASS="XRef">4</A>]. Program dock also minimizes energy based scores; description of minimization can be found in Meng, Gschwend, Blaney and Kuntz [<A HREF="Manual.4.html#25574" CLASS="XRef">6</A>].</P><P CLASS="Body"><A NAME="pgfId=2809"> </A>Several stand-alone docking-related programs exist. Program <A NAME="marker=2805"> </A><A HREF="Manual.26.html#38012" CLASS="XRef">cluster</A> generates alternative clusters of sphere centers within the active site. It uses as input, files from program <A NAME="marker=2810"> </A><A HREF="Manual.20.html#17338" CLASS="XRef">sphgen</A>. For energy scoring, ligand atom van der Waal attractive and dispersive factors and partial charges are also required.</P></DIV></DIV><DIV><H4 CLASS="Heading-4"><A NAME="pgfId=209"> </A>General Concepts</H4><P CLASS="Body"><A NAME="pgfId=211"> </A>This document is intended to give an overview of the ideas which form the basis of the dock suite of programs. It is not intended to be a reference manual or a user's guide for the programs, nor a substitute for all the papers written on dock. Rather, it gives a synopsis of the structure of the programs and concepts underlying the programs.</P><P CLASS="Body"><A NAME="pgfId=213"> </A>The dock suite of programs is designed to find favorable orientations of a ligand in a "receptor." It can be subdivided into (i) those programs related directly to docking of ligands and (ii) accessory programs. We limit the discussion in this section to only those programs and methods related to docking a ligand in a receptor. A typical receptor might be an enzyme with a well-defined active site, though any macromolecule may be used (e.g. a structural protein, a nucleic acid strand, a "true" receptor). We'll use an enzyme as an example in the rest of this discussion. </P><P CLASS="Body"><A NAME="pgfId=2924"> </A>The starting point of all docking calculations is generally the crystal structure of an enzyme from an enzyme-ligand complex. The ligand structure may be taken from the crystal structure of the enzyme-ligand complex or from a database of compounds, such as the <A NAME="marker=2940"> </A><A HREF="Manual.4d.html#31685" CLASS="XRef">Cambridge Crystallographic Database</A> [<A HREF="Manual.4.html#33051" CLASS="XRef">7</A>] or the Concord-generated [<A HREF="Manual.4.html#18443" CLASS="XRef">8</A>] set of coordinates from the <A NAME="marker=2936"> </A><A HREF="Manual.4d.html#21563" CLASS="XRef">Available Chemicals Directory</A>, or ACD, (from Molecular Design, Ltd., San Leandro, CA). The primary consideration in the design of our docking programs has been to develop methods which are both rapid and reasonably accurate. These programs can be separated functionally into roughly two parts, each somewhat independent of the other:</P><UL><LI CLASS="Body-Bullet"><A NAME="pgfId=221"> </A>Routines which determine the orientation of a ligand relative to the receptor.</LI><LI CLASS="Body-Bullet"><A NAME="pgfId=2969"> </A>Routines which evaluate (score) a ligand orientation.</LI></UL><P CLASS="Body"><A NAME="pgfId=225"> </A>There is a lot of flexibility. You can generate orientations outside of dock and score them with the dock evaluation functions. Alternatively, you can develop your own scoring routines to replace the functions supplied with dock. </P><P CLASS="Body"><A NAME="pgfId=227"> </A>The ligand orientation in a receptor site is broken down into a series of steps, in different programs. First, a potential site of interest on the receptor is identified. (Often, the active site is the site of interest and is known a priori.) Within this site, points are identified where ligand atoms may be located. A routine from the dock suite of programs identifies these points, called sphere centers, by generating a set of overlapping spheres which fill the site. Rather than using dock to generate these sphere centers, important positions within the active site may be identified by some other mechanism and used by dock as sphere centers. For example, the positions of atoms from the bound ligand may be used as these sphere centers. Or, a grid may be generated within the site and each grid point may be considered as a sphere center. Our sphere centers, however, attempt to capture shape characteristics of the active site (or site of interest) with a minimum number of points and without the bias of previously known ligand binding modes.</P><P CLASS="Body"><A NAME="pgfId=229"> </A>To orient a ligand within the active site, some of the sphere centers are "matched" with ligand atoms. That is, a sphere center is "paired" with an ligand atom. Many sets of these atom-sphere pairs are generated, each set containing only a small number of sphere-atom pairs. In order to limit the number of possible sets of atom-sphere pairs, a longest distance heuristic is used; (long) inter-sphere distances are roughly equal to the corresponding (long) inter-atomic ligand distances. A set of atom-sphere pairs is used to calculate an orientation of the ligand within the site of interest. The set of sphere-atom pairs which are used to generate an orientation is often referred to as a match. The translation vector and rotation matrix which minimizes the rmsd of (transformed) ligand atoms and matching sphere centers of the sphere-atom set are calculated and used to orient the entire ligand within the active site. </P><P CLASS="Body"><A NAME="pgfId=231"> </A>The orientation of the ligand is evaluated with a shape scoring function and/or a function approximating the ligand-enzyme binding energy. All evaluations are done on (scoring) grids in order to minimize the overall computational time. At each grid point, the enzyme contributions to the score are stored. That is, receptor contributions to the score, potentially repetitive and time consuming, are calculated only once; the appropriate terms are then simply fetched from memory. </P><P CLASS="Body"><A NAME="pgfId=233"> </A>The shape scoring function is an empirical function resembling the van der Waal attractive energy. To generate the shape score, the receptor terms from the grid point nearest to each non-hydrogen ligand atom are summed together. That is, the shape score is determined simply by the position of each ligand atom on the shape scoring grid.</P><P CLASS="Body"><A NAME="pgfId=235"> </A>The ligand-enzyme binding energy is taken to be approximately the sum of the van der Waal attractive, van der Waal dispersive, and Coulombic electrostatic energies. Approximations are made to the usual molecular mechanics attractive and dispersive terms for use on a grid. To generate the energy score, the ligand atom terms are combined with the receptor terms from the nearest grid point, or combined with receptor terms from a "virtual" grid point with interpolated receptor values. The score is the sum of over all ligand atoms for these combined terms. In this case, the energy score is determined by both ligand atom types and ligand atom positions on the energy grids. </P><P CLASS="Body"><A NAME="pgfId=237"> </A>As a final step, in the energy scoring scheme, the orientation of the ligand may be varied slightly to minimize the energy score. That is, after the initial orientation and evaluation (scoring) of the ligand, a grid-based rigid body simplex minimization is used to locate the nearest local energy minimum. The sphere centers themselves are simply approximations to possible atom locations; the orientations generated by the sphere-atom pairing, although reasonable, may not be minimal in energy.</P></DIV><DIV><H4 CLASS="Heading-4"><A NAME="pgfId=239">⌨️ 快捷键说明
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