Multiscale kinetic analysis of proteins

Abstract

The stochasticity of molecular motion results in the existence of multiple kinetically relevant pathways in many biomolecular mechanisms. Because it is highly demanding to characterize them for complex systems, mechanisms are often described with a single-pathway perspective. However, kinetic network analysis and sub-ensemble experimental insight are increasingly demonstrating not only the existence of competing pathways but also the importance of kinetic selection in biology. This review focuses on advances in multiscale kinetic analysis of proteins, which connects molecular level information from simulations to macroscopic data to characterize mechanistic reaction networks and the reactive flux through them. We describe a range of methods used and highlight several examples where kinetic modeling has revealed functional importance of pathway heterogeneity.

Keywords: Kinetic network analysis; Kinetic proofreading; Kinetic selection; Multiscale kinetic modeling; Multiscale modeling.

Figure 1.

Single pathway mechanism proposed for Cl-/H+ antiporter [1].

Figure 2.

Competing ion transport pathways in ClC-ec1.

Figure 3.

Shift in dominant pathways controlled by lower glutamic acid protonation state