Decades of extensive biochemistry and biophysics studies reveal that proteins are not rigid but ever-fluctuating entities. This project will examine the possible functional roles of the observed slow protein intramolecular dynamics in the context of cell regulation network dynamics. Cells regulate their dynamics and signaling through interconnected protein interaction networks. A biological network somewhat resembles a complex electric circuit. It processes input signals, makes decisions and functions against noisy environment. This exploratory project aims to identify general dynamic properties and physiological consequences of typical network motifs coupled to slow intramolecular dynamics. These motifs are abstracted from realistic systems with extensive experimental studies available. The researchers will apply the tools and concepts developed in network studies and perform deterministic and stochastic simulations to reveal the physiological functions of protein conformational fluctuations, which can be fully understood only in the context of cell regulation through multi-level coupling between molecular and cellular dynamics. This project will bridge researchers in several different fields, and add generate new insights into our understanding of the regulation and efficiency of biological processes. Examples of the latter include biosynthesis of desirable products such as biofuels. The proposed research will train highly needed multi-disciplinary students.
How can cells funcition robustly under noisy environment? Besides various regulatory networks, our mathematical analysis shows that some proteins are designed to response slowly and thus function as noise filters. For example, enzymes typically function optimally within a small range of pH values. A simple estimation reveals that for a bacterium the total number of free protons is around 15. A small fluctuation of the free proton numbers might lead to catastropic change of enzyme performances. Nature seems have solved this challenge by simply selecting enzymes that have finite response time to pH changes, thus filter out high frequency fluctuations. Through transiting among different conformations with different time scales, a single protein can also generate remarkable dynamic properties such as adaptation and oscillation. One can further tinker a few number of molecules of these properties together to form networks of various properties. As another example, bacteria have no eyes, nose, or hands. So how do they sense the environment? We studied the dynamics of the bacterial flagellar motor, a nanometer scale ion-drive protein motor. We showed how the motor can adjust its rotation direction by integrating input about the stimulant gradient and mechanical load on the motor. The latter two can be viewed as the "nose" and "hands" of a bacterium. The theoretical results provide important insignts not only on understanding how the structure-function relations of biological molecules are evolved and selected, but also on designing nanomachines and nanoscale elements. The latters face the same challenge that they need to function reliably under noisy environment and inputs.
