This document discusses methods for conformational analysis of molecules, which is needed to identify a molecule's lowest energy conformation. It describes systematic search methods that systematically explore all torsion angles combinations but are limited by computational time. It also describes model-building methods that construct conformations by joining molecular fragments. Available technologies for conformational analysis include software tools from Accelrys, Molecular Networks, OpenEye, Schrodinger, and Tripos.

1. Conformational Analysis
Systematic Method and Model-building Approach
Pinky Sheetal V
1801110004
M.tech Bioinformatics

2. Contents
• Introduction to Conformational Analysis
• Search Methods
• Systematic methods for exploring conformational
space
• Model building approach
• Available Technologies
• References

3. Conformational Analysis
• Conformation generally means structural arrangement
• Conformational analysis is needed to identify the ideal conformation of a
molecule
• The biological activity of molecules is strongly dependent on their
conformation
• Done by exploring the energy surface of a molecule and determining the
conformation with minimum energy
• Needed:
– Conformational space
– Search method
– An energy determination method

4. Conformational Space
• clash-free space - atoms are not in self-collision
Conformational search methods
• Systematic search algorithms
• Model-building methods
• Random approaches – Generates conformers by random perturbation of
Cartesian coordinates or the torsion angles of rotatable bonds
• Distance geometry – Determines the lower and upper distances for all pairs
of atoms in the molecule and the distance matrix is generated
• Molecular dynamics

5. Systematic Method
• Simplest
• Deterministic
• Grid search
Assumption: All bond lengths and angles remain fixed throughout the calculation
Identify all rotatable bonds
Rotate bonds through
360degrees by fixed increments
Advantages
• A deterministic approach, hence
Generate a new conformation a systematic exploration of
conformational space
Energy minimization
• Can be used for small molecules
or systems with 10-15 bonds
Minimum energy conformation
All possible torsion angles
combinations have been generated
and minimized

6. Shortcomings
Combinatorial explosion:
Θ is the dihedral angle chosen for the bond i
Example –
• 3 rotatable bonds
– 30 degree increment
– Conformers generated = 1728
– Time = 29 min
• 5 rotatable bonds
– 30 degree increment
– Conformers = 248832
– Time = 69 hours
• Time for 7 rotatable bonds = 415 days
• Explores large regions with high energy
• Not good for highly flexible molecules
 Therefore its time consuming and cannot be used for large system

7. Search tree
Eliminates the time consuming energy minimization stage for structures that have a very high
energy or some other problem 0 Root node
1 3
2
4
13 15
14
Conformers with severe intra-molecular clashes, i.e. interatomic van der Waals contact
energy greater than 10 kcal/mol are removed.

8. Model-building method
• Construct conformations of molecules by joining together three-dimensional
structures of molecular fragments
• Assumptions:
1. Each fragment must be conformationally independent of the other
fragments in the molecule
2. Conformations stored for each fragment must cover the range of structures
that are observed in fully constructed molecules
• Substructure search algorithm
– Substructure searching is finding a mapping for a query to a target molecule.
– In other words, no bonds are broken and no new bonds are formed.

9. Available technologies
• CatConf, or ConFirm, from Accelrys that is part of the Discovery Studio
pharmacophore modeling protocols and tools provides two different search modes, fast
(systematic search) and best (distance geometry) .
• The program systems CORINA and ROTATE available from Molecular Networks.
• OMEGA from OpenEye Scientific Software is a fast systematic, knowledge-based
method.
• MacroModel from Schrodinger is a very well-known and widely used force field-based
molecular modeling package and offers a variety of methods for conformation
generation.
• CONFORT was developed by Prof. Pearlman, University of Texas, Austin and is
distributed by Tripos. CONFORT performs an exhaustive conformational analysis of a
molecule.
• Some open source packages, such as Open Babel (http://openbabel.org) or RDKit
(http://www.rdkit.org), provide means to generate sets of molecular conformations.

10. References
• Christof H. Schwab, Conformations and 3D pharmacophore searching, DOI:
10.1016/j.ddtec.2010.10.003
• http://www.biochem.vt.edu/modeling/conformation.html
• Elber, R. and Karplus, M. (1987) Multiple Conformational States of Proteins: A
Molecular Dynamics Analysis of Myoglobin, Science 235: 318-321.
• Leach, A.R. (1991) A Survey of Methods for Searching the Conformational Space of
Small and Medium-Sized Molecules, in, Reviews in Computational
Chemistry, Vol.2, Lipkowitz, K.B. and Boyd, D.B., eds. VCH Publishers, New York, pp.
1-55.
• http://www.chem.memphis.edu/parrill/chem8711/2004/Conformational%20Search.pdf
• I-Jen Chen and Nicolas Foloppe, Conformational Sampling of Druglike Molecules with
MOE and Catalyst: Implications for Pharmacophore Modeling and Virtual Screening, J.
Chem. Inf. Model. 2008, 48, 1773–1791
• Molecular Modelling Principles and Applications, Andrew R. Leach, 2nd
Edition, Prentice Hall

11. Thank you