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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> Conformation Search</TITLE></HEAD><BODY BGCOLOR="#ffffff"><H2 CLASS="Heading-3"><A NAME="pgfId=646"> </A><A NAME="31662"> </A><A NAME="marker=11653"> </A>Conformation Search</H2><P CLASS="Body"><A NAME="pgfId=9901"> </A>The conformation of a flexible molecule may be searched or relaxed using the <A HREF="Manual.19.html#22201" CLASS="XRef">flexible_ligand</A> option. Only the torsion angles are modified, not the bond lengths or angles. Therefore, the input geometry of the molecule needs to be of good quality. A structure generated by CONCORD is sufficient.</P><P CLASS="Body"><A NAME="pgfId=44902"> </A>The user may request a conformation search using the <A HREF="Manual.19.html#29408" CLASS="XRef">torsion_drive</A> parameter and/or torsion minimization using the <A HREF="Manual.19.html#32915" CLASS="XRef">torsion_minimize</A> parameter. The torsion angle positions reside in an editable file (see <A HREF="Manual.4c.html#25230" CLASS="XRef">flex_drive.tbl on page 111</A>) which is identified with the <A HREF="Manual.19.html#20042" CLASS="XRef">flex_drive_file</A> parameter. Internal clashes are detected during the torsion drive search based on the <A HREF="Manual.19.html#36936" CLASS="XRef">clash_overlap</A> parameter, which is independent of scoring function.</P><P CLASS="Body"><A NAME="pgfId=44889"> </A>If <A HREF="Manual.19.html#37217" CLASS="XRef">multiple_ligands</A> are being processed, then the <A HREF="Manual.19.html#19540" CLASS="XRef">flexible_bond_maximum</A> cutoff is used to discard overly flexible molecules.</P><P CLASS="Body"><A NAME="pgfId=44890"> </A>When scoring is requested, the user has the option of computing intramolecular terms using the <A HREF="Manual.19.html#27914" CLASS="XRef">intramolecular_score</A> parameter. For the sake of speed, only the interactions between segments is considered. If a segment has not moved, then the contribution of its interaction with the receptor to the intermolecular score is not recalculated. If any two segments have not moved, then the contribution of their interaction to the intramolecular score is not recalculated.</P><P CLASS="Body"><A NAME="pgfId=44933"> </A>The treatment of flexible molecules will be elaborated further. The first stage of processing is the <A HREF="Manual.f.html#36626" CLASS="XRef">Identification of Rigid Segments</A>. The second stage of processing is the conformation search, at which point the user has the choice of two methods. An <A HREF="Manual.f.html#37908" CLASS="XRef">Anchor-First Search</A> may be selected, in which a molecule conformation is constructed and minimized one segment at a time, starting from an anchor segment. Alternatively, a <A HREF="Manual.f.html#15938" CLASS="XRef">Simultaneous Search</A> will be performed, in which the entire molecule conformation is constructed and minimized in one step.</P><DIV><H3 CLASS="Heading-4"><A NAME="pgfId=44832"> </A><A NAME="36626"> </A>Identification of Rigid Segments</H3><P CLASS="Body"><A NAME="pgfId=12338"> </A>A flexible molecule is treated as a collection of rigid segments. Each segment contains the largest set of adjacent atoms separated by non-rotatable bonds. Segments are separated by rotatable bonds.</P><P CLASS="Body"><A NAME="pgfId=44978"> </A>The first step in segmentation is ring identification. All bonds within molecular rings are treated as rigid. This classification scheme is a first-order approximation of molecular flexibilty, since some amount of flexibility can exist in non-aromatic rings. To treat such phenomenon as sugar puckering and chair-boat hexane conformations, the user will need to supply each ring conformation as a separate input molecule.</P><P CLASS="Body"><A NAME="pgfId=44839"> </A>Additional bonds may be specified as rigid by the user. Please refer to the subsequent section, <A HREF="Manual.f.html#21011" CLASS="XRef">Manual specification of non-rotatable bonds</A>.</P><P CLASS="Body"><A NAME="pgfId=12389"> </A><MAP NAME="Manual-4"></MAP><IMG SRC="Manual-4.gif" USEMAP="#Manual-4" ALIGN="RIGHT">The second step is flexible bond identification, and is illustrated in <A HREF="Dock.Manual.3.html#65333" CLASS="XRef">Figure 2</A> for a sample molecule. Each flexible bond is associated with a label defined in an editable file (see <A HREF="Manual.4b.html#26494" CLASS="XRef">flex.defn on page 110</A>). The parameter file is identified with the <A HREF="Manual.19.html#17403" CLASS="XRef">flex_definition_file</A> parameter. Each label in the file contains a definition based on the atom types (and chemical environment) of the bonded atoms. Each label is also flagged as minimizable. Typically, bonds with some degree of double bond character are excluded from minimization so that planarity is preserved. Each label is also associated with a set of preferred torsion positions. The location of each flexible bond is used to partition the molecule into rigid segments. A segment is the largest local set of atoms that contains only non-flexible bonds.</P><DIV><H6 CLASS="Heading-5"><A NAME="pgfId=44854"> </A><A NAME="21011"> </A>Manual specification of non-rotatable bonds</H6><P CLASS="Body"><A NAME="pgfId=44845"> </A>The user can specify additional bonds to be non-rotatable, to supplement the ring bonds automatically identified by dock. Such a technique would be used to preserve the conformation of part of the molecule and isolate it from the conformation search. Non-rotatable bonds are identified in the <A HREF="Manual.41.html#19711" CLASS="XRef">SYBYL MOL2 format</A> file containing the molecule. The bonds are designated as members of a STATIC BOND SET named RIGID. Please see <A HREF="Manual.41.html#19711" CLASS="XRef">SYBYL MOL2 format on page 99</A> for an example of such an identification.</P><P CLASS="Body"><A NAME="pgfId=45017"> </A>Creation of the RIGID set can be done within sybyl. With the molecule of interest loaded into sybyl, select the Build/Edit->Define->Static Set->Bond command. Then select each bond by picking the adjacent atoms. When the "Set Name" dialog comes up, supply the name "RIGID" in capital letters. When the "Comment String" dialog comes up, enter any text you wish. Write out the molecule to file.</P><P CLASS="Body"><A NAME="pgfId=45033"> </A>Alternatively, the RIGID set can be entered into the MOL2 file by hand. To do this, go to the end of the MOL2 file. If no sets currently exist, then add a SET identifier on a new line. It should contain the text "@<TRIPOS>SET". On a new line add the text "RIGID STATIC BONDS <user> **** Comment". On the next line enter the number of bonds that will be included in the set, followed by the numerical identifier of each bond in the set.</P></DIV></DIV><DIV><H3 CLASS="Heading-4"><A NAME="pgfId=11903"> </A><A NAME="37908"> </A><A NAME="marker=11902"> </A>Anchor-First Search</H3><P CLASS="Body"><A NAME="pgfId=10012"> </A>The anchor-first search is an efficient divide-and-conquer algorithm based on the method of Leach and Kuntz [<A HREF="Manual.14.html#30470" CLASS="XRef">19</A>] and the greedy algorithm. It is specified using the <A HREF="Manual.19.html#28389" CLASS="XRef">anchor_search</A> parameter.</P><P CLASS="Body"><A NAME="pgfId=45905"> </A><MAP NAME="Manual-5"></MAP><IMG SRC="Manual-5.gif" USEMAP="#Manual-5" ALIGN="RIGHT">An anchor segment is selected from the rigid segments in an automatic fashion (see <A HREF="Manual.f.html#38957" CLASS="XRef">Manual specification of anchor segment</A> to override this behavior). As illustrated in <A HREF="Dock.Manual.3.html#17441" CLASS="XRef">Figure 3</A> for a sample molecule, the molecule is divided into segments that overlap at each rotatable bond. The segment with the largest number of heavy atoms is selected as the anchor. If the <A HREF="Manual.19.html#18588" CLASS="XRef">multiple_anchors</A> parameter is set, then all segments which pass the <A HREF="Manual.19.html#34097" CLASS="XRef">anchor_size</A> cutoff are tried separately as anchors.</P><P CLASS="Body"><A NAME="pgfId=45928"> </A><MAP NAME="Manual-6"></MAP><IMG SRC="Manual-6.gif" USEMAP="#Manual-6" ALIGN="RIGHT">When an anchor has been selected, then the molecule is redivided into non-overlapping segments, which are then arranged concentrically about the anchor segment. This process is illustrated in <A HREF="Dock.Manual.3.html#27605" CLASS="XRef">Figure 4</A> for a sample molecule. Segments are reattached to the anchor according to the innermost layer first -- and within a layer -- the largest segment first.</P><P CLASS="Body"><A NAME="pgfId=10053"> </A>The anchor is processed separately (either oriented, scored, and/or minimized). The anchor position can be optimized prior to the conformation search with the <A HREF="Manual.19.html#42603" CLASS="XRef">minimize_anchor</A> parameter.</P><P CLASS="Body"><A NAME="pgfId=51389"> </A>The remaining segments are subsequently re-attached during the conformation search. See <A HREF="Dock.Manual.3.html#15583" CLASS="XRef">Figure 5</A> for a diagram of the anchor-first docking process. The conformation search corresponds to steps 2 and 3 which form a complete cycle. An extensive analysis of the docking can be performed by setting the <A HREF="Manual.19.html#22766" CLASS="XRef">write_partial_structures</A> parameter which causes all partially-built structures to be written out during the conformation search. Two files will be generated for each cycle of the conformation search. For the first cycle, one file will contain the anchor orientations from step 1 in <A HREF="Dock.Manual.3.html#15583" CLASS="XRef">Figure 5</A> and the other file will contain the pruned orientations from step 2. For all subsequent cycles, one file will contain the conformationally-expanded configurations from step 3, and the other file will contain the pruned configurations from step 2. The names of the files will be based on the name given for the ligand output file, but will have a sequence of numbers appended to it as shown in <A HREF="Manual.f.html#41750" CLASS="XRef">Table 6</A>.</P><DIV><MAP NAME="Manual-7"></MAP><IMG SRC="Manual-7.gif" USEMAP="#Manual-7"></DIV><H3 CLASS="Table"><A NAME="pgfId=51431"> </A>Table 6. <A NAME="41750"> </A>Filename Construction when Writing Partial Structures</H3><TABLE><TR><TH ROWSPAN="1" COLSPAN="2"><P CLASS="Normal"><A NAME="pgfId=51404"> </A>Files are name-A-LL-S-E.ext, with the components defined as follows:</P></TH></TR><TR><TD ROWSPAN="1" COLSPAN="1"><P CLASS="Normal"><A NAME="pgfId=51408"> </A>name</P></TD><TD ROWSPAN="1" COLSPAN="1"><P CLASS="Normal"><A NAME="pgfId=51410"> </A>The base file name of the ligand output file.</P></TD></TR><TR><TD ROWSPAN="1" COLSPAN="1"><P CLASS="Normal"><A NAME="pgfId=51412"> </A>A</P></TD><TD ROWSPAN="1" COLSPAN="1"><P CLASS="Normal"><A NAME="pgfId=51414"> </A>Anchor number (single digit).</P></TD></TR><TR><TD ROWSPAN="1" COLSPAN="1"><P CLASS="Normal"><A NAME="pgfId=51416"> </A>LL</P></TD><TD ROWSPAN="1" COLSPAN="1"><P CLASS="Normal"><A NAME="pgfId=51418"> </A>Layer number (two digits).</P></TD></TR><TR><TD ROWSPAN="1" COLSPAN="1"><P CLASS="Normal"><A NAME="pgfId=51420"> </A>S</P></TD><TD ROWSPAN="1" COLSPAN="1"><P CLASS="Normal"><A NAME="pgfId=51422"> </A>Segment number within layer (single digit).</P></TD></TR><TR><TD ROWSPAN="1" COLSPAN="1"><P CLASS="Normal"><A NAME="pgfId=51424"> </A>E</P></TD><TD ROWSPAN="1" COLSPAN="1"><P CLASS="Normal"><A NAME="pgfId=51426"> </A>Ensemble number within cycle (1=conformation expanded; 2=pruned).</P>⌨️ 快捷键说明
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