Surface-facilitated trapping by active sites: From catalysts to viruses.

Trapping by active sites on surfaces plays important roles in various chemical and biological processes, including catalysis, enzymatic reactions, and viral entry into host cells. However, the mechanisms of these processes remain not well understood, mostly because the existing theoretical descriptions are not fully accounting for the role of the surfaces. Here, we present a theoretical investigation on the dynamics of surface-assisted trapping by specific active sites. In our model, a diffusing particle can occasionally reversibly bind to the surface and diffuse on it before reaching the final target site. An approximate theoretical framework is developed, and its predictions are tested by Brownian dynamics computer simulations. It is found that the surface diffusion can be crucial in mediating trapping by active sites. Our theoretical predictions work reasonably well as long as the area of the active site is much smaller than the overall surface area. Potential applications of our approach are discussed.

Role of Intrinsically Disordered Regions in Acceleration of Protein-Protein Association.

Although intrinsically disordered proteins and intrinsically disordered regions (IDRs) in folded proteins are not able to form stable structures, it is known that they play critically important roles in various biological processes. However, despite multiple studies, the molecular mechanisms of their functions remain not fully understood. In this work, we theoretically investigate the role of IDRs in acceleration of protein-protein association processes. Our hypothesis is that, in protein pairs with several independent binding sites, the association process goes faster if some of these binding sites are located on IDRs or connected by IDRs. To test this idea, we employed analytical modeling, numerical calculations, and Brownian dynamics computer simulations to calculate protein-protein association reaction rates for the ERK2-EtsΔ138 system, belonging to the RAS-RAF-MEK-ERK signaling pathway in living cells. It is found that putting a binding site on IDR accelerates the association process by a factor of 3 to 4. Possible molecular explanations for these observations are presented, and other systems that might use this mechanism are also mentioned.

Theoretical Investigation of the Mechanisms of ERK2 Enzymatic Catalysis.

ERK2 are protein kinases that during the enzymatic catalysis, in contrast to traditional enzymes, utilize additional interactions with substrates outside of the active sites. It is widely believed that these docking interactions outside of the enzymatic pockets enhance the specificity of these proteins. However, the molecular mechanisms of how the docking interactions affect the catalysis remain not well understood. Here, we develop a simple theoretical approach to analyze the enzymatic catalysis in ERK2 proteins. Our method is based on first-passage process analysis, and it provides explicit expressions for all dynamic properties of the system. It is found that there are specific binding energies for substrates in docking and catalytic domains that lead to maximal enzymatic reaction rates. Thus, we propose that the role of the docking interactions is not only to increase the enzymatic specificity but also to optimize the dynamics of the catalytic process. Our theoretical results are utilized to describe experimental observations on ERK2 enzymatic activities.