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

摘要

Many proteins contain multiple folded domains separated by flexible linkers, and in order to understand how such multi-domain proteins function, we need to be able to describe how these domains are oriented in space. We have used the three-domain protein TIA-1 as an example to combine molecular simulations with biophysical experiments to describe the structural and dynamical properties of a multi-domain protein. We show that while standard simulations do not lead to good agreement with the experimental data, we can improve the agreement substantially by tuning a single parameter in the model that describes the interaction between protein and water. We can gain further information about the system by a more direct integration of the data, and we find that we can provide a detailed and robust description of the relative location of the different domains in TIA-1. The method is general and will be useful to study the relationship between structure, dynamics and function in multi-domain proteins in other systems.