Continuous interdomain orientation distributions reveal components of binding thermodynamics,

by Yang Qi, Jeff Martin, Adam Barb, Francois Thelot, A. Yan, B. R. Donald*, and Terry Oas*

*Corresponding authors

Journal of Molecular Biology (2018)

[PDF Reprint, PDF at Journal, Preprint at bioRxiv, Errata ]

Abstract:

The flexibility of biological macromolecules is an important structural determinant of function. Unfortunately, the correlations between different motional modes are poorly captured by discrete ensemble representations. Here, we present new ways to both represent and visualize correlated interdomain motions. Interdomain motions are determined directly from residual dipolar couplings (RDCs), represented as a continuous conformational distribution, and visualized using the disk-on-sphere (DoS) representation. Using the DoS representation, features of interdomain motions, including correlations, are intuitively visualized. The representation works especially well for multidomain systems with broad conformational distributions. We use this new paradigm to study the interdomain motions of staphylococcal protein A, which is a key virulence factor contributing to the pathogenicity of S. aureus. We capture the smooth transitions between important states and demonstrate the utility of continuous distribution functions for computing components of binding thermodynamics. Such insights allow the dissection the dynamic structural components of functionally important intermolecular interactions.

Full reference: Journal of Molecular Biology 2018; 430(18, Part B) 3412-3426

Watch Videos of talks:

  1. We have a YouTube playlist devoted to this topic.
  2. Structure of a Protein with a Flexible Linker: Continuous Distribution of Interdomain Orientations Derived from NMR RDCs (Youtube)
    CASP SIG on Modeling Conformational Ensembles (2024).
  3. Applied math seminar, May 2019:
    [Video Lecture (YouTube), Abstract]
  4. [Video lecture (Duke Maths Dept.), Abstract]
  5. Redefining Structure: New Approaches for
    (a) Deep Topological Sampling of Protein Structures, and
    (b) Continuous Probability Density Function for Biomolecular Interdomain Orientations,
    by Yang Qi, Jeff Martin, Adam Barb, Francois Thelot, Anthony Yan, Terry Oas*, and B. R. Donald*.
    Invited talk
    Experimental NMR Conference (ENC). Pittsburgh, PA. April 12, 2016.
    [ PDF]

Errata

There are two typos in our JMB paper, unfortunately introduced by the printer:
Eq. (10) is missing a parentheses, so P2θ should read P2(θ).
Eq. (15) is missing a minus sign. It should read ΔS = − RT ∫ (P2(θ) ln P2(θ) − P1(θ) ln P1(θ)) dθ

History

The version on BioArxiv preprint server is below. It is the penultimate submission for the referees. You can also see our conference presentation below. bioRxiv 200238; (2017)
doi: https://doi.org/10.1101/200238
[Abstract, PDF, Supplementary Material]