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Related Concept Videos

Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
¹H NMR of Conformationally Flexible Molecules: Temporal Resolution00:52

¹H NMR of Conformationally Flexible Molecules: Temporal Resolution

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...
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
¹H NMR of Conformationally Flexible Molecules: Variable-Temperature NMR01:15

¹H NMR of Conformationally Flexible Molecules: Variable-Temperature NMR

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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AutoSIM: Redesigning and automating umbrella sampling for biomolecular conformational transitions.

Mitradip Das1, Ravindra Venkatramani1

  • 1Department of Chemical Sciences, Tata Institute of Fundamental Research, Dr. Homi Bhabha Road, Colaba, Mumbai 400005, India.

The Journal of Chemical Physics
|July 7, 2025
PubMed
Summary

This study introduces AutoSIM, a novel automated umbrella sampling (US) method. AutoSIM enhances free energy surface (FES) calculations for biomolecular processes by optimizing reaction coordinate sampling and improving FES projection quality.

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Area of Science:

  • Computational Chemistry
  • Biophysics
  • Molecular Dynamics Simulations

Background:

  • Umbrella sampling (US) is crucial for free energy surface (FES) calculations but sensitive to reaction coordinate (RC) selection and simulation timescales.
  • Current US methods require a priori knowledge of RCs, limiting their application.

Purpose of the Study:

  • To develop an automated US scheme (AutoSIM) that overcomes limitations in RC selection and improves FES projection quality.
  • To enable FES calculations independent of predefined RCs or end states.

Main Methods:

  • Implemented a redefined US scheme within the AutoSIM algorithm, automating US runs from a single non-equilibrated trajectory.
  • AutoSIM leverages statistical insights for enhanced sampling equilibration and RC convergence.
  • Combined statistics from multiple US runs to systematically assess and refine FES projections.

Main Results:

  • AutoSIM successfully generated FES sections for functional conformational transitions in biomolecules.
  • Validated AutoSIM by comparing FES projections of alanine dipeptide and ubiquitin with unbiased simulations.
  • Applied AutoSIM to determine the energetics of HIV-1 protease's open-to-closed conformational transition.

Conclusions:

  • AutoSIM provides a robust and automated approach to FES calculations using US.
  • The method enhances the reliability and efficiency of studying biomolecular conformational changes.
  • AutoSIM facilitates the investigation of complex biological systems like HIV-1 protease.