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Conformational Dynamics of Proteins: Insights from Structural and Computational Studies

Student: Lin Liu    Advisor: Ivet Bahar, Angela Gronenborn

Crystal contacts between neighboring proteins suppress the mobility of particular residues in the crystal lattice.

Proteins are not static; they undergo both random thermal fluctuations near a given equilibrium state, and transitions between different sub-states. These motions are usually intricately connected to the function of the protein. Therefore, understanding the dynamics of proteins is important to gain insights into the mechanisms of many biological phenomena. Only the combination of structure and dynamics does allow for describing a functional protein (or biological molecule) properly.

Atomic motions can be divided into three basic components: the timescale of the motion, its amplitude, and its direction. There exist several methods that have been developed to study protein dynamics, not only experimental methods such as NMR relaxation, fluorescence, and single-molecule FRET, but also structure-based computational methods such as molecular dynamics (MD) simulations and normal mode analysis. However, each method only informs about different aspects of protein dynamics. For these reasons, I combined experimental and computational approaches in my work. My research is centered on computational and experimental studies of protein dynamics. I carried out full atomic (MD) simulations and coarse-grained analyses (using elastic network models - ENMs) as computational approaches, and used NMR as well as X-ray crystallography on the experimental side.

With regard to the study of equilibrium dynamics of proteins, i.e., the fluctuations accessible under equilibrium conditions, I carried out two specific investigations:

Another area of interest concerned the phenomena of "domain swapping." We investigated the molecular basis of this unusual multimerization using a broad range of approaches. A systematic analysis of a large set of domain-swapped structures was performed, as well as an experimental investigation on a particular protein:

Overall, both equilibrium and non-equilibrium dynamics of proteins were studied in my thesis, using multiple biophysical and computational approaches. The results show that computational and experimental methods yield complementary results and are ideally used in combination for evaluating protein dynamics and gaining insights into the molecular basis of observed phenomena.

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