Conformation Analysis
General remarks
The menu cnf contains various options to
generate and analyze conformations of structures in a rather
general sense. For a basic, though somewhat outdated, general
description see
Tutorial for the conformation module.
In this exercise we show how to generate conformations of a
molecule and an example how to analyze those.
A file of the Molecule Trimethoprim (trimethoprim.mab)
can be found in the moloc/dat directory.
Setup of a Conformation Run
- Start Moloc
- Read in the structure trimethomprim '.../g/m'
- Enter the conformation generator 'cnf/c'. These
menus are handled best by treating point by point (if needed) from
left to right.
- 'k' This allows to use either a single structure
or an already existing conformation library as starting structures.
The second option may be useful in cases where only a single feature
is subjected to variation, but in a whole set of already existing
conformations.
- 'm' method: we choose 'grid'
in which a (multidimensional) grid of dihedral angle values is
systematically run through.
- 'e' A list of entries (in our case just one)
is presented from which to choose the one to be handled.
- 'r' This option is to define rings or loops
in case the 'ring/loop' method was chosen, we skip
this point.
- 'g' Definition of the dihedral angle grid.
Upon clicking this point a new menu 'grid search'
is entered. The highlighted menu title indicates that picking (bonds)
is required.
- Pick one of the bonds between the two rings. It will turn read
and the atoms of the smaller fragment are highlighted as the set to
be moved under change of the dihedral angle. You are asked whether
you agree with this set or want inversion. This is irrelevant here
but may be of importance when you make the analysis with a background
entry. Just choose keep.
- Now a slider appears with which you can define how many angles
should be taken. Choosing a high value is only advisable if the
number of bonds to rotate about is small.
- Repeat the previous procedure with all bonds you want (here e.g.
the second bond between the rings).
- Exit the bond specification menu.
- 'b' Since we have no background this point is
skipped.
- 'f,c' We don't want neither to specify fixed
atoms nor constraints, here.
- 'i' By choosing interactive mode you can watch
the program at work. It will just write a conformation library
trimethoprim.mcl which is also kept in memory.
- 'b' For batch mode the program writes several
files: trimethoprim.s.mcl, trimethoprim.Gntr, and
trimethoprim.Fpar which contain all the information needed
to run the job. Then the job is started. It produces the same
conformation library trimethoprim.mcl.
- Under Windows the job has to be explicitly started by issuing
the command 'Mlbch -f -c trimethoprim', where the
program name has to be proceeded by the path of the Moloc bin
directory!
The method of stochastic conformation generation
is straightforward and for a description of the
ring/loop method see the first
reference on
conformational analysis.
Analyze Conformations
- Start Moloc
- Read in the conformation library trimethoprim.mcl
'.../g/k/m'. If you have specified just the two
bonds and used default parameters for the generation the program
will tell you that there are 7 conformations. Only a single
representant is displayed, however.
- Enter the conformation menu 'cnf'.
- Enter the multi display menu 's'. You will be
asked specify libraries (here just one), and enter a new menu:
- Click 's' and select
'conformation per library' to be confronted with
a list of all conformations.
- Choose 'all' to see the whole lot that have been generated.
This picture is usually chaotic and of little use.
- To obtain a more useful representation, we have to exit from this
menu.
- Enter the modification menu 'm'.
- Choose 'r', rigid body match which throws you
in the set specification menu.
- Specify atoms 'a' ant pick the the ones of
the pyrimidine ring, or substituents 's' and pick
the connecting methylene carbon and its neighbor on the pyridine
ring. This will tell the program, that you want those atoms (marked
with white rings) superimposed.
- Upon leaving the set menu Moloc presents a list of the available
conformations to choose the target from.
- Moloc will also ask for a variable name, because the rmsd of the
superimpositions is a conformation specific value. In this particular
case the quantity is not very informative. (You can delete it in
'cnf/d/t'.)
- As an aside click 'p' to obtain a table of
parameters. The item superposition is set to
'move' which signifies that the superposition is
not only calculated but also applied to the conformations. The
possibility 'on' calculates best superposition and
enters the result into the data field, but without applying the
transformation to the conformations. Finally 'off'
will calculate rmsd values for the specified set without performing
a superposition calculation.
- Exit.
- Now the multi display will be more informative, showing the
various orientations of the phenyl ring.
- Enter the analysis menu 'a' in order to get an
impression of the diversity of the 7 conformations.
- Choose 'r' to calculate an rmsd table and, when
asked, choose 'similarity analysis'.
- Again the set menu is entered in order to specify the set of
atoms that participate.
- Choose the whole entry ('e' and pick) and exit.
You will now be asked for a file name for the table. The default
'-' will write the table to the text port.
- Now the list of conformations appears and lets you specify the
conformations for which the table should be calculated. Choose all!
- The resulting similarity matrix (table) is presented as a
hierarchical tree and you are asked, whether you want it calculated
by complete or single linkage.
- Now you are thrown into the cluster analysis menu
'clan' the handling of which is treated in the
Diversity tutorial. There you can produce,
with option 'l', a divers subset which, when
'select centers' is specified will show up, upon exit, as a
select-set on the conformations.
- With your select-set generated, exit.
- To produce a reduced library of divers conformations choose
'y' (yank set into library) specify the selection
set and a color for the library representant.
- If needed store the new library.
It should be mentioned, that the same type of analysis can be
performed in menu 'mch/l' in case the conformations
are given as separate entries which may originate from an external
program or from expanding a conformation library via
'cnf/m/e'. The result is then an entry-set, the
entries of which can be stored e.g. in a multi-entry file (several
possible formats).