Local dynamics in protein function and specificity / Julian E. Fuchs

• VerfasserIn: Fuchs, Julian E.
• Place / Publishing House: 2013
• Year of Publication: 2013
• Language: English
• Classification: 35.06 - Computeranwendungen; 35.76 - Aminosäuren. Peptide. Eiweiße; 35.74 - Enzyme. Hormone. Vitamine
• Physical Description: 339 Bl.; Ill., graph. Darst.
• Notes: Enth. u.a. 60 Veröff. d. Verf. aus den Jahren 2008 - 2013

ger: Proteins are inherently flexible under physiological conditions.<br />Hence, dynamics are crucial to understand their function in detail. The current perspective on proteins is mostly limited to static views available from X-ray crystallography, although these structures represent only one possible state among the thermodynamically accessible ensemble. Nuclear magnetic resonance spectroscopy is an experimental technique capable of providing valuable insight into dynamic properties of biological macromolecules. Still, this approach is limited in system size, throughput and resolution. Computer simulations of proteins provide a unique alternative to gain insights into their dynamics in solution. Using current high performance computing facilities, biomolecular motions can be traced at atomistic resolution on the femto- to microsecond scale.<br />Within my PhD thesis I focus on the role of protein dynamics on function and specificity. Thereby, I investigate the role of mutations, modifications, and ligand binding on protein dynamics using computational techniques. Changes in the systems' dynamics are correlated to experimental data concerning biological function, binding affinity and specificity. Investigated systems cover enzymes including the large family of proteases, the well-studied phenylalanine hydroxylase and influenza neuraminidase. Furthermore, the major birch pollen allergen bet v 1 and the transcription factor NF-?B were investigated.<br />Striking correlations between protein dynamics and their biological properties were observed, proving that a static view on proteins is insufficient to fully understand their biological roles. Both function and specificity critically depend on intrinsic dynamic features of proteins. A large part of protease substrate specificity can be understood solely on the basis of backbone dynamics. Thereby, any sort of enthalpic information was not considered, complementing the established mostly static view of protease-substrate recognition. In the course of these studies I established the first metric for protease specificity that can be used to quantify and compare subpocket and total specificity of proteases of any catalytic type. I also showed the direct applicability of information on substrate specificity for drug design via calculation of protease similarity trees giving access to off-target predictions.<br />I contributed to development of new computational methods for measuring sidechain flexibility, entropy calculation and estimation of cooperative effects in protein-ligand interactions in several further successful projects. Within a book contribution on ensemble docking I linked information on protein dynamics to structure-based virtual screening.<br />Further publications comprise work on DNA structure and recognition as well as ab initio structure prediction for alkylglycerol monoxygenase.