Combining NMR Spectroscopy and Molecular Dynamics Simulation to Investigate the Structure and Dynamics of Membrane-Associated Proteins

Abstract

Nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations are both powerful methods for the investigation of the structure and dynamics of biological membranes and membrane proteins but like every scientific method they both have their inherent advantages and disadvantages. Fortunately, these strengths and weaknesses are rather complementary to each other. Typically, MD simulations perform best on model systems with a limited number of molecules, while NMR methods can be applied to much larger and more complex systems. Furthermore, MD simulations are very limited in the size of the systems and the timescales which can be simulated, while NMR is an ensemble technique that is sensitive to a very broad window of timescales. However, interactions of the like molecules of the ensemble are difficult to study which does not pose a problem in MD simulations. In complex systems that do not provide atomistic resolution, tracing an NMR result to its molecular origin can be very difficult while MD simulations offer a complete atomistic representation of the system. This all argues that a combination of the two methods can produce synergies that lead to a much deeper understanding of a specific research question. In this chapter, we address how experimental results can be used to guide MD simulation setup and validate its results and how these results can be used to obtain a much more detailed picture of the processes that occur in the investigated system. The combined use of both methods is illustrated on several examples of investigations on the human N-Ras protein, which represents a membrane-associated small GTPase.