TY  - GEN
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/7669/
Y1  - 2007///
ID  - heidok7669
N2  - The mechanisms through which proteins achieve their functional three-dimensional structure starting from a string of amino acids, as well as the manner in which the interactions between different structural elements are orchestrated to mediate function are largely unknown, despite the large amount of data accumulating from theoretical and experimental studies. One clear view emerging from all these studies is that function is a result of the intrinsic protein dynamics and flexibility, namely the motions of its well-defined structural elements and their ability to change their position and shape in space to allow large conformational transitions necessary for the function.  Simulation techniques have been increasingly used over the past years in the endeavour to solve the structure-function puzzle as they have proven to be powerful tools to investigate the dynamics of proteins. However, extracting useful dynamical information from trajectories thus generated in order to draw functionally relevant conclusions is not always straight forward, especially when the protein function involves concerted movements of entire protein domains. This is due to the high dimensionality of the energy surface the proteins can explore. Therefore, a decrease in complexity is to be desired and can be achieved in principle by reducing the number of dimensions to the ones capturing only the dominant motions of the protein.  To this purpose, in this thesis two different dimensionality reducing techniques, namely Principal Component Analysis and Sammon Mapping are applied and compared on four proteins that undergo conformational changes with different amplitudes and mechanisms. In particular, the present thesis tackles the large conformational change occurring during the recovery stroke of myosin, using these methods and rigidity analysis algorithms in the attempt to elucidate in atomic detail the structural mechanism underlying the function of this protein that couples ATP hydrolysis to the mechanical force needed to achieve muscle contraction. The results presented in this thesis show the successful applicability of certain dimensionality reducing methods to large conformational changes and their suitability in analyzing and dissecting dynamical transitions in computationally generated trajectories. The findings regarding the recovery stroke step in the myosin cycle are consistent with experimental data coming from mutational studies and confirm the previously postulated communication mechanism between the active sites of the protein, thus representing a major contribution to the field of molecular motors and a strong evidence of the importance of theoretical studies in complementing the experimental investigations. 
KW  - Structural changes 
KW  -  Proteins 
KW  -  Recovery-Stroke
TI  - Analysis of Large-Scale Structural Changes in Proteins with focus on the Recovery Stroke Mechanism of Myosin II
A1  - Mesentean, Sidonia E.
AV  - public
ER  -