Microsecond molecular dynamics simulations and NMR studies of dynamic protein-protein and protein-lipid complexes
소속 :
연사 : prof.Matthias Buck(Case Western Reserve University)
일시 : 2017-05-04 16:30 ~
장소 : 500동, 목암홀
The EphA2:SHIP2 SAM domain heterodimer is a dynamic protein complex: It is now recognized that protein-protein interactions are often dynamic, especially if the binding affinities are only moderately strong. Dynamics originate in part from the interconversion between structures of the protein complex, e.g. one bound state that is in equilibrium with several alternate configurations. We determined the structure of such a complex using NMR restraints and saw the transitions between different configurations in microsecond length all-atom molecular dynamics simulations. Recently, we also studied the dissociation process of mutant complexes which had a weakened primary interaction interface. Those simulations suggested that there is no single dissociation pathway, but that the separation first involves transitions to binding interfaces with even fewer/weaker contacts. The same molecular dynamics study also revealed that a substantial change in pico-nanosecond internal protein dynamics accompanies protein complex dissociation and is a sizeable component of the thermodynamics of dissociation as an entropy contribution. How these dynamic features contribute to diverse biological functions is discussed.
Rho and Ras GTPases are localized to the inner side of the cellular membrane by lipid anchors. Recently, it has become clear that also the catalytic core region of these proteins interacts with specific lipids in the membrane. These interactions determine the orientation of the core region and thus access to GTPase partner binding proteins. In a joint experimental and computational study, we discovered that the shape/topology of the protein plays a major role in determining orientational preferences of Ras at the membrane. Plexin receptors are unusual receptors in that they bind directly with small GTPases. We have solved x-ray and NMR structures of plexin-GTPase complexes and have carried out multi-microsecond simulations of the complexes, again showing that these are highly dynamic entities. This project relates to studies carried out in collaboration with Dr. Gyu Rie Lee and others in Prof. Seok’s laboratory. The Galaxy suite of loop and protein core predictions is used to model the GTPase binding domain of plexin, showing that the loops of this ubiquitin-like protein can be modeled to considerable correspondence with the NMR data.
Rho and Ras GTPases are localized to the inner side of the cellular membrane by lipid anchors. Recently, it has become clear that also the catalytic core region of these proteins interacts with specific lipids in the membrane. These interactions determine the orientation of the core region and thus access to GTPase partner binding proteins. In a joint experimental and computational study, we discovered that the shape/topology of the protein plays a major role in determining orientational preferences of Ras at the membrane. Plexin receptors are unusual receptors in that they bind directly with small GTPases. We have solved x-ray and NMR structures of plexin-GTPase complexes and have carried out multi-microsecond simulations of the complexes, again showing that these are highly dynamic entities. This project relates to studies carried out in collaboration with Dr. Gyu Rie Lee and others in Prof. Seok’s laboratory. The Galaxy suite of loop and protein core predictions is used to model the GTPase binding domain of plexin, showing that the loops of this ubiquitin-like protein can be modeled to considerable correspondence with the NMR data.
