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¹H NMR of Conformationally Flexible Molecules: Temporal Resolution00:52

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At room temperature, the chair conformer of cyclohexane undergoes rapid ring flipping between two equivalent chair conformers at a rate of approximately 105 times per second. These two chair conformers are in equilibrium. The rapid ring flipping results in the interconversion of the axial proton to an equatorial proton and an equatorial to the axial proton. Such interconversions are too rapid and cannot be detected on the NMR timescale. Hence, the NMR spectrometer cannot distinguish between the...
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¹H NMR of Conformationally Flexible Molecules: Variable-Temperature NMR01:15

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The axial and equatorial protons in cyclohexane can be distinguished by performing a variable-temperature NMR experiment. In this process, except for one proton, the remaining eleven protons are replaced by deuterium. The deuterium substitution avoids the possible peak splitting caused by the spin-spin coupling between the adjacent protons. The remaining proton flips between the axial and equatorial positions.
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Most chemical reactions in cells require enzymes—biological catalysts that speed up the reaction without being consumed or permanently changed. They reduce the activation energy needed to convert the reactants into products. Enzymes are proteins, that usually work by binding to a substrate—a reactant molecule that they act upon.
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In an organic molecule, free rotation about the carbon-carbon single bond results in energetically different conformers of the molecule. Due to this rotation, called the internal rotation, ethane has two major conformations — staggered and eclipsed.
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BCL::Conf: small molecule conformational sampling using a knowledge based rotamer library.

Sandeepkumar Kothiwale1, Jeffrey L Mendenhall1, Jens Meiler2

  • 1Department of Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN 37232 USA.

Journal of Cheminformatics
|October 17, 2015
PubMed
Summary
This summary is machine-generated.

Predicting small molecule shapes is key for drug discovery. A new method uses fragment rotamers from databases to rapidly generate likely molecular conformations, improving accuracy in drug design.

Keywords:
Conformation samplingFragment-basedKnowledge-basedRotamer-library

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Area of Science:

  • Computational chemistry
  • Structural biology
  • Drug discovery

Background:

  • Protein-target interactions depend on small molecule 3D structure.
  • Accurate conformational prediction is vital for drug discovery algorithms like docking and 3D-QSAR.

Purpose of the Study:

  • To develop a novel method for rapid and accurate prediction of small molecule conformational space.
  • To create a database of frequently sampled small molecule fragments and their likely conformations ('rotamers').

Main Methods:

  • Derived a database of small molecule fragments from experimental structures (Cambridge Structure Database, Protein Data Bank).
  • Stored likely fragment conformations as 'rotamers', considering multi-bond correlations and substituent effects.
  • Generated conformational ensembles by recombining fragment rotamers using a Monte Carlo search strategy.
  • Benchmarked BCL::Conf against other conformer generators (Confgen, Moe, Omega, RDKit).

Main Results:

  • BCL::Conf achieved high accuracy, recovering experimental conformations within 2 Å RMSD for 99% of molecules in the Vernalis benchmark.
  • The method effectively captures correlations between torsion bonds and substituent effects.
  • Demonstrated superior performance in recovering experimentally determined protein-bound conformations compared to existing methods.

Conclusions:

  • The fragment 'rotamer' approach provides a robust and efficient method for small molecule conformational sampling.
  • BCL::Conf enables accurate generation of diverse conformational ensembles for drug discovery.
  • This method facilitates integration into computational biology programs like Rosetta for enhanced drug design capabilities.