title: Linking 3D and 2D binding kinetics of membrane proteins by multiscale simulations.
abstract: Membrane proteins are among the most functionally important proteins in cells. Unlike soluble proteins, they only possess two translational degrees of freedom on cell surfaces, and experience significant constraints on their rotations. As a result, it is currently challenging to characterize the in situ binding of membrane proteins. Using the membrane receptors CD2 and CD58 as a testing system, we developed a multiscale simulation framework to study the differences of protein binding kinetics between 3D and 2D environments. The association and dissociation processes were implemented by a coarse-grained Monte-Carlo algorithm, while the dynamic properties of proteins diffusing on lipid bilayer were captured from all-atom molecular dynamic simulations. Our simulations show that molecular diffusion, linker flexibility and membrane fluctuations are important factors in adjusting binding kinetics. Moreover, by calibrating simulation parameters to the measurements of 3D binding, we derived the 2D binding constant which is quantitatively consistent with the experimental data, indicating that the method is able to capture the difference between 3D and 2D binding environments. Finally, we found that the 2D dissociation between CD2 and CD58 is about 100-fold slower than the 3D dissociation. In summary, our simulation framework offered a generic approach to study binding mechanisms of membrane proteins.
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York, 10461.
authors.forename: Zhong-Ru
authors.initials: ZR
authors.lastname: Xie
authors.forename: Jiawen
authors.initials: J
authors.lastname: Chen
authors.forename: Yinghao
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000465:Algorithms; D018801:CD2 Antigens / Q000737:chemistry / Q000378:metabolism*; D018968:CD58 Antigens / Q000737:chemistry / Q000378:metabolism*; D004058:Diffusion; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D011485:Protein Binding
chemical_list: D018801:CD2 Antigens; D018968:CD58 Antigens
keywords: binding kinetics; coarse-grained model; membrane proteins; multiscale simulation