Combining molecular dynamics simulations with small-angle X-ray and neutron scattering data to study multi-domain proteins in solution

Author(s)Andreas Haahr Larsen

by Andreas Haahr Larsen, Yong Wang, Sandro Bottaro, Sergei Grudinin, Lise Arleth, Kresten Lindorff-Larsen

Many proteins contain multiple folded domains separated by flexible linkers, and the ability to describe the structure and conformational heterogeneity of such flexible systems pushes the limits of structural biology.

Using the three-domain protein TIA-1 as an example, we here combine coarse-grained molecular dynamics simulations with previously measured small-angle scattering data to study the conformation of TIA-1 in solution.

We show that while the coarse-grained potential (Martini) in itself leads to too compact conformations, increasing the strength of protein-water interactions results in ensembles that are in very good agreement with experiments.

Make more money selling and advertising your products and services for free on Ominy market. Click here to start selling now

Subscribe now to remove this ad, read unlimited articles, bookmark your favorite post and soo much more

We show how these ensembles can be refined further using a Bayesian/Maximum Entropy approach, and examine the robustness to errors in the energy function. In particular we find that as long as the initial simulation is relatively good, reweighting against experiments is very robust.

We also study the relative information in X-ray and neutron scattering experiments and find that refining against the SAXS experiments leads to improvement in the SANS data. Our results suggest a general strategy for studying the conformation of multi-domain proteins in solution that combines coarse-grained simulations with small-angle X-ray scattering data that are generally most easy to obtain.

These results may in turn be used to design further small-angle neutron scattering experiments that exploit contrast variation through 1H/2H isotope substitutions.

This paper was published at
Access the full paper Here

Ominy science editory team

A team of dedicated users that search, fetch and publish research stories for Ominy science.

Enable notifications of new posts    OK No thanks