A Structure-free Method for Quantifying Conformational Flexibility in proteins.

Virginia M Burger,Collin M Stultz,Daniel J Arenas

doi:10.1038/srep29040

Virginia M Burger, Collin M Stultz + Show 1 more

Open Access

https://doi.org/10.1038/srep29040

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Abstract

All proteins sample a range of conformations at physiologic temperatures and this inherent flexibility enables them to carry out their prescribed functions. A comprehensive understanding of protein function therefore entails a characterization of protein flexibility. Here we describe a novel approach for quantifying a protein’s flexibility in solution using small-angle X-ray scattering (SAXS) data. The method calculates an effective entropy that quantifies the diversity of radii of gyration that a protein can adopt in solution and does not require the explicit generation of structural ensembles to garner insights into protein flexibility. Application of this structure-free approach to over 200 experimental datasets demonstrates that the methodology can quantify a protein’s disorder as well as the effects of ligand binding on protein flexibility. Such quantitative descriptions of protein flexibility form the basis of a rigorous taxonomy for the description and classification of protein structure.

Highlights

Induced conformational fluctuations enable proteins to sample a range of structures under physiologic conditions
Our overall approach was to construct ensembles for each protein, generate a theoretical ensemble average small-angle X-ray scattering (SAXS) profile for each ensemble, and input these data into our Radius of Gyration Distribution (RgD) algorithm to determine whether the RgD model can produce entropies that are consistent with our understanding of the relative disorder of these systems
The resulting SAXS profiles are input to the RgD algorithm to determine whether the method can differentiate proteins according to their flexibility

Summary

Introduction

Induced conformational fluctuations enable proteins to sample a range of structures under physiologic conditions. To determine whether the RgD formalism has the sensitivity needed to quantify protein flexibility using SAXS intensity profiles, we applied the method to model protein systems representing different degrees of disorder.

Results

Conclusion