Protein Conformational and Interaction Dynamics by Molecular Dynamics Simulations and Nuclear Magnetic Resonance Experiments
The function of proteins is inherently linked to their atomic motions. Such fluctuations may occur at a range of timescales from femtoseconds to minutes and involve a variety of spatial components. In order to identify, study and eventually understand these processes we must implement a variety of techniques that report on the different timescales and atomistic details of relevance. In this talk, we describe the application of all-atom Molecular Dynamics (MD) simulations as well as combination of such simulation methods with NMR experiments, as a paradigm for the study of protein dynamics. We examine three cases of systems with great interest from a biological and pharmacological perspective.
The first is a transmembrane protein complex composed of the G-protein coupled receptor (GPCR) rhodopsin and its G-protein intracellular counterpart transducin. Based on the analysis of our μsec-timescale simulation trajectory starting from a docked conformation of the complex, we report a highly dynamic interface that is alternating between distinct interdomain orientations. The second part is a comparative study of two intrinsically disordered peptides, Aβ(1-40) and Aβ(1-42), which are the main constituents of amyloid plaques found in the brain of patients with Alzheimer's disease (AD). We use enhanced-sampling simulations to describe the conformational ensembles adopted by these flexible peptides and relate our simulation results with experimental results from NMR. The third study focuses on a fusion protein designed to study the structure, dynamics and thermodynamics of the interactions between ubiquitin and ubiquitin-interacting motifs (UIMs). We use standard NMR spectroscopy techniques to solve the solution structure of the complex and a variety of NMR relaxation methods to characterize its plasticity at a range of timescales from picoseconds to milliseconds. We complement the NMR-based structure and dynamics analysis through performing multiple all-atom Molecular Dynamics simulations at the μsec timescale starting form the NMR ensemble in order to obtain a plausible structural model for the observed dynamics.
