Proteins are biological macromolecules that control virtually all aspects of cellular functions, ranging from enzyme catalysis, response to external stimuli, to control of cell cycle and cell fate decision. For function, proteins have evolved to possess unique three-dimensional (3D) structural properties. This project focuses on an important newly recognized class of proteins that exploit highly flexible 3D structures for function. These proteins include so-called intrinsically disordered proteins (IDPs) that account for about one-third of all eukaryotic proteins and are key components of cellular signaling and regulatory networks. This project will develop efficient computational methods for simulating flexible proteins and uncover the fundamental principles of how structural disorder mediates protein function. The new computational tools will be made available to the broad scientific community and can be applied to study biomolecular dynamics and interactions in general. Besides training of graduate and undergraduate students, the PI will contribute to various outreach programs in western Massachusetts that engage women and other under-represented minorities in STEM fields. He will also help expand an informal science education project known as the "Molecular Playground", which installs interactive molecular displays in public spaces such as schools, museums, shopping malls and airports. This project will add much-needed contents with protein dynamics, such as to illustrate the fascinating phenomenon how extreme conformational flexibility of IDPs support function.
The overarching research objective of this project is to determine the fundamental principles that allow flexible proteins such as IDPs to undergo rapid binding-induced folding or unfolding for viable cellular signaling. Greater utilization of flexible proteins such as IDPs have been associated with increasingly sophisticated signaling in complex multicellular organisms. However, the frequent requirement of large-scale conformational transitions for binding flexible proteins can lead to a potential kinetic bottleneck detrimental to effective cellular signaling. It is hypothesized that long-range electrostatic interactions between enriched charges on IDPs and their binding targets play a key role in promoting facile binding. A specific hypothesis to be tested is that long-range electrostatic forces not only accelerate IDP encounter, but also promote folding-competent encounter topologies to allow efficient folding upon encounter. This project will also tackle an emerging phenomenon known as regulated unfolding in cellular signaling and determine how transient hydrophobic interactions may reduce transition barriers and contribute to efficient coupled binding, folding and unfolding in Bcl-2 family proteins. To test these hypotheses, new GPU-accelerated, implicit solvent-based atomistic simulation techniques will be developed to enable efficient calculation of the free energy, pathway and kinetics of binding-induced large-scale protein conformational transitions. Results from equilibrium and kinetic simulations will be validated using existing mechanistic and kinetic data as well as new measurements performed in collaboration with experimental labs. This project is supported by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences with partial co-funding from the Chemical Theory, Models and Computational methods (CTMC) Program in the Division of Chemistry.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
