PROTEIN CONFORMATIONAL AND INTERACTION DYNAMICS BY MOLECULAR DYNAMICS SIMULATIONS AND NUCLEAR MAGNETIC RESONANCE EXPERIMENTS
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.
