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Moloc: Molecular Modelling on UNIX Workstations: 18 Conformational Libraries
Conformational Libraries
This menu provides tools to deal with conformation
libraries. Such a library consists of a structure defined by
its topology and a set of conformations. In addition,
various properties may be attributed to a library (e.g.
energy, radius of gyration), such that every conformation
has a value attributed to each of those. Libraries are stored
on disk in a non-ASCII format, but various public formats
that contain structures with several conformations can be
entered into Moloc and can be handled with the options of
this menu. Most frequently libraries are used for united
atom structures, but handling of C-alpha structures is also
implemented.
,: peptide representation
To indicate the orientation of peptide links in Calf
structures, the representation of the structure by con
necting linked Calfs is augmented by an additional line
between the calculated positions of the nitrogen and
oxygen atoms of the peptide. The auxiliary display is
initiated by picking the structure. Picking with the
middle button removes the auxiliary display.
c: new conformational libraries
Several methods are provided to generate a new library
of local minimum conformations of a given structure by
automated procedures.
p: new positional libraries
A special case of libraries are positional libraries in
which conformation signifies position of a structure in
an environmental context. Correspondingly, such librar
ies need an associated environment structure. This menu
provides facilities to generate such libraries.
m: modify libraries
Modifications of libraries such as adding or removing
conformations, reorienting conformations or even topol
ogy changes can be performed here.
t: delete libraries
A list of libraries currently held in memory is pre
sented in which the ones to be removed can be marked.
d: data generation on conformations
Various types of conformation-dependent data can be
calculated.
a: analyze libraries
Associated data of a conformation library provide a
basis for generating subsets of conformations, for sta
tistical analysis etc. Subsets can be deleted or used
to generate new libraries.
s: show conformations
Several conformations of libraries can be displayed
simultaneously according to various selection criteria.
b: browse conformations
The conformations of a library can be displayed one by
one and be examined for various, mostly structural,
properties. This menu is identical with the browse
option for a set of entries (
Display).
In the corresponding help text the term entry now has to be inter
preted as conformation.
l: link
New structures can be generated by starting from pairs
of conformations from two positional libraries. The
program tries to connect them by a fitting intermediate
linking fragments.
n: noe
Analysis of noe data
18.1 Conformation Generator [generator]
Several methods (modes) to generate conformation libraries
are provided. Most of these require typically much
computation time, such that batch operation is recommended.
Except for the trivial option n, one has to make sure to
complete a set of specifications necessary for the chosen
method before starting a conformation run (check on the menu
items). This includes adjusting the parameters with the p
option.
k,K: from single conformation
Conformational runs can start from a single initial
conformation (k) or from a set (library) of several
conformations (K). The second case is most relevant for
grid search runs, where only a few bond rotations are
varied on a set of existing conformations.
m: specify method
There is a choice of three methods:
Stochastic run in which the atomic positions are ran
domly varied starting from the last minimized struc
ture.
Ring/loop run for cyclic structures, where the initial
positions of a ring or loop (part of the cycle) of atoms
are initially arranged in various shapes, compatible
with the size of the ring, see Helv.Chim.Acta 71, 1429-
1441 (1988).
Grid search in which several bonds (or atom pairs) are
specified about which parts of the structure are
rotated by specified angles before energy minimization
is performed.
e: specify entry
The sample entry, for which the conformational analysis
is needed, is identified here.
r: specify ring or loop
Needed only for ring/loop runs. The atoms that form the
ring to be initially varied are specified here.
g: specify torsional-angle grid
For grid runs only. The bond (atom pairs) about which
initial rotation is requested are specified here. The
program also asks for the atom sets subject to the ini
tial rotation as well as for the number of values for
the rotation angles.
b: specify background
A background can be specified, which is held constant
but participates in the energy calculation. This pro
vides a simple tool for docking type studies.
f: set fixed atoms
A set of atoms can be specified, which is held fixed
during minimization. This is needed for loop runs but
can be useful in other cases as well.
c: set constraints
Various types of constraints can be applied during min
imization. However, in the final minimization con
straints are always released!
i: interactive run
The calculation can be done in interactive mode. This
is only recommended in special cases, when little CPU-
time is needed (which is almost never the case).
b: batch run
The specified analysis is started as a batch run. Sev
eral files are written to specify the method. The
result is a library of .mcl format. Output and log files
are also written.
p: set parameter
The complete set of parameters regarding conformational
runs is presented and can be modified.
n: new one-conformer libraries
Creates new one-conformer libraries from a set of
entries. Each new library has the corresponding entry
as its representant and sole conformation.
18.2 Fragment Positioning [positioning]
This menu serves to set up jobs to generate libraries of
positioned fragments in a background environment. To start
with, an entry (positions entry) must be created, the
elements of which define the coordinate at which the
fragments are initially (prior to energy minimization)
placed. This is the purpose of the first few menu items.
Option t sets thresholds relevant for some of these points,
while option p addresses parameters relevant for the actual
fragment positioning. Most points of this menu need be
addressed to complete the setup of a positioning analysis.
k,K: from single conformation
Positional runs can start from a single initial confor
mation (k) or from a set (library) of several conforma
tions (K).
e: specify environment (background)
A environment can be specified, which is held constant
but participates in the energy calculation. It may be
useful to use a more extended environment for generat
ing the positions than for the actual calculation,
where calculation speed may be significantly enhanced
by using the minimal necessary environment.
s: specify surface atoms
The set menu is entered to specify the atoms that define
the surface on the background entry onto which the sam
ple molecules need to be positioned. The background
must be specified in advance!
c: create positions
From the specified surface atoms a set of positions are
created at which the sample entries will be placed ini
tially. This set can be pruned with the help of the fol
lowing three options.
d: remove densely packed positions
Any pair of positions that are closer spaced than the
minimal distance is replaced by a single position in
between them. This process takes the closest pair at
the time and proceeds until the distance of this pair
exceeds the threshold distance. The value of the
threshold distance can be set in option t.
o: remove outside positions
The positions and the environment atoms are put in a
single entry. of this entry a dotted surface is calcu
lated using a solvent radius of the surface distance as
specified in option t. At the end the environment atoms
are removed again together with the positions that
carry at least one surface point.
r: remove positions interactively
The set menu is entered in order to specify the posi
tions that are not needed. Only positions can be picked
here. Upon leaving the set menu, the designated posi
tions are removed.
p: select positions entry
In case that several (initial) positions entries have
been prepared, this serves to select the one that
should be taken for the next calculation.
m: specify molecules (entries) to be positioned
Several entries can be specified to undergo a position
ing analysis. A separate batch run will be set up for
each chosen entry.
i: interactive run
It is in principle possible to run a calculation inter
actively. However, in view of the fact that such calcu
lations are often very demanding in CPU-time, using
this option is discouraged.
b: batch run
For each specified sample entry a job is submitted car
rying the entry name. It is the users responsibility to
avoid unwanted file-overwriting by choosing appropriate
entry names!
t: set thresholds
The threshold distance parameter is operative under
option d. It determines whether a pair of generated
surface points is replaced by a single one. This hap
pens for every pair of points with distance below this
threshold.
The surface distance parameter is operative under
option o. It determines the coarseness under which the
surface is considered with respect to groves.
p: set parameter
The complete set of parameters regarding positional
runs is presented and can be modified.
18.3 Library Modifications [modify]
This menu provides various ways of modifying existing
conformational libraries.
i: insert entries
Entries held in memory can be inserted as conformations
into existing a library. The topology of the entries
must be the same as the one of the library, but label
ling or arrangement of atoms may differ.
k: delete conformations
Deletes conformations from libraries.
m: merge libraries
Inserts the conformations of several libraries into a
single target library. The target library is first
specified, and subsequently the libraries to be
inserted. Duplication of the same conformation can be
avoided. The duplicate check is governed by the parame
ters of option p.
t: change topology
A restricted-functionality building menu is entered in
which topology changes can be made on the representa
tive entry of a library. These changes are automati
cally propagated to all conformations of the library.
This option is not available for Calf structures.
u: unique conformations
Makes a library free of duplicates. Two conformations
are considered to be equivalent if their energy differ
ence, rmsd and (for C-alpha structures) rmsa is smaller
than the corresponding tolerance. These tolerances are
set in the p option. The parameters superposition and
symmetry influence the rmsd calculation (move option of
superposition is ignored). For a cluster analysis of
conformational diversity see also the library analysis
menu.
k: convert to Calf
From the chosen library of protein conformations a new
library is generated the representative of which is the
Calf structure resulting from the protein representa
tive. The conformations of the Calf library correspond
to the ones of the full protein library.
a: convert Calf to full protein
From the chosen Calf library a new all-atom protein
library is generated.
b: convert Calf to backbone
From the chosen Calf library a new protein library is
generated which only contains backbone atoms (including
carbonyl oxygens and beta carbons).
r: rigid body match
A rigid body multi-match of all conformations onto a
single one is performed. First the user specifies the
set of atoms that will participate in the match, then
the target conformation is chosen. As a result all con
formations are superimposed onto the target conforma
tion such that the mutual rmsd for all pairs of
conformations is minimized.
e: expand library
For each conformation of the library a separate entry
to appear in Moloc is produced. The entries carry the
name of the library and an additional index number. All
new entries form an entry set with the name of the
library.
p: parameter settings
Parameter relevant for superposition and geometry-com
parison can be altered here.
For each specification made a new data field is introduced
into the library which contains the corresponding value for
each conformation. The user is informed on the text port
about the name of the field and the range of values
encountered.
d: distance
Calculates the distance between two atoms. Pick two
atoms or a bond.
a: angle
Calculates the angle of any three atoms. Pick the cen
ter first and then 2 other atoms.
t: torsion angle
Calculates the torsion angle of any four atoms. Pick
the four atoms in the desired sequence.
p: pyramidality
Calculate the pyramidality of any for atoms. Pick the
center first then the remaining three. The sign of the
result will depend on the order of picking.
j: j-coupling
Calculates the vicinal j-coupling between H atoms. Pick
two H atoms or pick a C-C bond for all H-H coupling over
that bond. Only vicinal H-C-C-H coupling without any
double bonds can be calculated (see C.A.G. Haasnoot,
F.A.A.M. de Leeuw & C. Altona, Tetrahedron 36, 2783-
2792 (1980))
For Calf structures a new menu is entered to calculate
vicinal j-coupling of the backbone.
r: rmsd
Calculates rmsd of a subset of atoms with respect to a
specified conformation. The result of this option may
depend heavily on the values of the superposition and
symmetry parameters.
p: parameters for rmsd
Get help directly from the table.
c: combine
Calculates a new value from two existing ones. Addition
(+), subtraction (-), multiplication (*) and division
(/) arei supported. A form pops up, in which one selects
the two quantities to be combined, and the desired
operation. In addition a name to characterize the
result can be entered.
t: delete values
In a pop up-box one can select the values to be deleted.
e: examine data
In a submenu calculated values can be statistically
analyzed and displayed.
The following options apply only to Calf libraries:
s: angle deviation
The root mean square deviation of the peptide backbone
angles phi and psi (rmsa) for a given set of residues is
calculated for every conformation. The reference
against which the calculation is performed is defined
by selecting a target conformation. The end angles are
not included.
f: peptide backbone angles
Peptide backbone angles phi and psi can be calculated.
A pop up selection offers the possibility to choose
phi, psi or both. Which residues are affected is deter
mined by the setting of the [1,*]-switch at the end of
this menu.
2: secondary structure
Calculates secondary structure content, helix or sheet
or both. Which residues are affected is determined by
the setting of the [1,*]-switch at the end of this menu.
1,*: single, sequence-selected monomers
This toggle switch determines whether residue selection
in option f and 2 are made by picking a single monomer
(1) or by specifying chain-id and sequence numbers (*).
In the former case values are only calculated for the
picked residue. In the latter case values for each
specified residue are calculated, thus, the number of
new data fields will be once or twice the number of res
idues specified.
The conformational data associated with a library can be
examined by several statistical methods. If non-graphical
data are produced the program asks for a file name (default:
standard output).
t: table
A table of selected data items is written values into a
file. The energy is always printed in first place as an
identifier.
h: histogram
A histograms is produced for the values selected. The
program Gr2d is used for display.
2: 2D correlation
A two-dimensional display of two selected variables
drawn against each other is produced. The points are
labeled by the energy.
a: average
The arithmetic mean, the root mean square, and the
standard deviation are calculated.
p: average of periodic values
Calculates average and correlation of periodic values.
The arithmetic mean of periodic values (like torsion
angles) are useless. To give a more useful average the
arithmetic mean of unit vectors with corresponding
angles is taken. The angle of this mean vector is the
average of the value, the absolute value of the mean
vector is the correlation of the value (David J.
Detlefsen, V. Thanabal, V.L. Pecoraro, and Gerhard Wag
ner, Biochemistry 30 (1991) p9040-9046). A correlation
of 1 signifies that all values are the same, a correla
tion of 0 means that the values are spread evenly over
the period. The period is always 360.
18.5 Library Analysis
Conformational libraries can be analyzed in various ways.
In several cases the result is a subset of the library. Such
subsets can be combined by logical operation to yield new
subsets. Furthermore, a set can be yanked into a new library.
Some of the menu items make only sense if subsets exist
already.
s: screen
Creates library subset by applying a criterium to a
particular data item. The program asks for the data
item and for a selection criterium. There are 5 types of
criteria: upper limit, lower limit, range, the n high
est, and the n lowest. They are entered by '<UPPER\q,
'>LOWER\q, \qLOWER-UPPER\q, \q[HIGHEST\q, and \q]LOWEST\q
respectively. For ranges if the upper limit is smaller
than the lower limit, the conformations with values
outside the range are selected. To use that feature on a
value different from energy, you need to calculate such
a value with the data generation option (
see above).
b: boolean
Combines subsets of the library. There are 3 binary
operators, namely & (and), | (or) and ^ (xor), and the
unary operator ! (not). The subsets are referenced by
numbers displayed on standard output (normally start up
window) on return. Any combination of 1 or 2 subsets are
allowed. Example: '!0 & 1\q means not in subset 0 but in
subset 1.
y: yank set into library
Creates a new library with the conformations of a sub
set. The program asks you for the subset, color and name
of the new library. All sets and screen values are
inherited from the parent library.
h: H bonds
The H-bond patterns of all conformations are calcu
lated. These patterns include the H-bonds within the
structure of the library as well as H-bonds between the
library structure and all entries that are put into the
active state. A new menu is entered to examine these
patterns.
r: rmsd table
A table of all pair-wise rmsd is written into a file.
First the set of atoms must be specified which partici
pate in the rmsd calculation. Then, the program asks
for the output file name (default: standard output).
Finally, a list of all conformations is presented from
which one must specify the ones that should be consid
ered in the analysis. the dimension of the resulting
table is determined by the number of specified confor
mations.
e: examine values
In a submenu calculated values can be statistically
analyzed and displayed (see
see above).
t: print set table
Writes a table of sets in a file. The program asks for a
file name (default: standard output), and for the sets
to be written to the file.
d: delete sets
Deletes subsets. The program asks you, which subsets
should be deleted.
m: multi display
Displays multiple conformations on the screen. The pro
gram asks for the conformations to be displayed.
p: set parameters
A table of conformation parameters pops up. They may be
changed.
18.6 Show Conformations
Several conformations from the libraries specified upon
entering this menu can be displayed simultaneously in
various colors. Initially only representatives are
displayed. The conformations to be displayed can be selected
according to various criteria.
.: display
Deleting an entry will result in an abortion of the
multi-display!
s: select conformations
Conformations to be displayed simultaneously can be
selected one by one from a selector which may present
either the conformations of all libraries taken
together. Alternatively, a selector for each library
may be presented in turn, each one containing just con
formations of the library. Finally, conformations can
be chosen by specifying sets of conformations (if any
are defined).
v: select by value
Conformations of libraries to be displayed are speci
fied by setting upper and lower limits on previously
calculated data values. A first a pop-up box allows to
choose the library. A second pop-up box is then pre
sented to select the value of interest, and finally,
upper and lower limit can be set on two sliders.
r: pick new representative
From the shown conformations one can define a new rep
resentative for the library by picking. This conforma
tion will then change its color to white.
c: change colors
A multi-valued selector (enabling toggling through the
available colors) is presented containing either the
currently visible conformations (all or by library) or
the selected sets. For the items in the selector inde
pendent colors can be chosen.
d: set of displayed conformations
A new set will be defined which contains all currently
displayed conformations.
e: composed entry
A new entry will be defined which is a composition of
all currently displayed conformations, each taken as a
separate fragment to the new entry.
18.7 Linking
This menu link fragments by linkers out of a library, A
background entry can be given with which the linker can not
intersect. A minimization with this background entry can be
performed. All option are set by the p option or read in as a
start up file (.Moloc) The result can be analyzed with the
option a.
l: link fragments
Linkers are fitted between pairs of fragments. The
fragments are select by a pop up box. If the entry is
the representative of a library all conformation are
taken. As linkers all structures from a specified .cif-
file are taken (see option p). In the interactive mode,
they can also be specified interactively. All linkers
that fit within the limits defined in the parameter
table (see option p) are taken, unless they violate a
collision criterion. Collisions are checked between
linker and fragments, between the two fragments, and
between linker and background entry (if selected). All
implicit hydrogen atoms are potential link sites.
Finally, the resulting molecules are submitted to
energy minimization, unless a negative number of itera
tions is specified.
c: combinatorial linking
Entries are linked together with a single bond. It
makes possible combinations of the linear connection
frg1 - frg2 - ... - frg n within the tolerances. The add
single bond is between the connection atoms. There must
be defined exactly 1 connection atom per fragment in an
atom set. The tolerance checked are bond length and
bond angle. The fragments given as selections of
libraries The output are libraries which belong to the
entry set with the same name as the job-name. It is
stored in a .cif file and can be analyzed with the
option a.
p: set linker parameters
In a new menu one can set all the parameters, that con
trol the linker. name: name of the resulting linked
entry. %f format for fragment name (2 possible), %l for
linker name (only 1). bond & dihedral angle tolerance:
maximal violation of the pseudo bond & dihedral angle
resp. distance tolerance: maximal violation of the dis
tance. minimal & maximal distance: range of the dis
tance between the centre of mass of the 2 fragments.
a: analyze an entry set
This menu allows you to measure distances, calculate
scoring function, and browse a complete entry set
including different conformations in libraries. You can
select some entries/conformations by these values. Sin
gle entries will be converted into one-conformation
libraries. This newly created libraries can be deleted
when you leave the menu, however, that will delete also
the measured values.
s: calculate scoring function
The scoring function, an estimate for the free energy
of binding of the complex, is calculated in a parallel
batch job. All active entries together are taken as the
receptor entity and each conformation in the selected
set is taken as the actor entity (inhibitor, agonist,
etc.). An empirical formula of the type used by Boehm
(J-CAMD 8, 243, 1994, JACS 114, 10697, 1992) is
applied.
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