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Conformational Analysis
Systematic Method and Model-building Approach




                          Pinky Sheetal V
                            1801110004
                       M.tech Bioinformatics
Contents
• Introduction to Conformational Analysis
• Search Methods
• Systematic methods for exploring conformational
  space
• Model building approach
• Available Technologies
• References
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
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
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
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
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.
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.
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.
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
Thank you

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Conformational analysis

  • 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