The Energy Landscapes of Protein Folding and Function: Connecting Theory and Experiments

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Many cellular functions rely on interactions among proteins and between proteins and nucleic acids. The overall goal of this project, jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Biological Physics Program in the Division of Physics in the Mathematical and Physical Sciences Directorate, is to decipher the first principles of self-assembly processes of biomolecules with the ultimate aim to understand the principles of cellular network organization from a physical viewpoint. Energy landscape theory and the funnel concept have advanced the understanding of the robust self-assembly of a single protein chain into its uniquely native structure. For small proteins, the reduced models that are minimally energetically frustrated will be generalized to study the effects of local geometrical details, non-native interactions, and desolvation on folding mechanisms. Larger proteins, which have much more complex energy landscapes, will be studied to characterize their folding mechanisms, kinetics, pathways, and intermediates. Folding alone, however, is not sufficient for a full picture of function. Function requires change of structure and specific recognition to form complexes and to enable the wireless communication in the cell. This research will address these two aspects by: (1) Exploring the conformational transitions associated with function using generalized reduced models that incorporate the multiple stable conformations of the protein. Unlike macroscopic machines, proteins are biological machines that can locally break and then reassemble during function. Models for global structural transformations, such as allostery and molecular communication, will be developed. They involve large-scale motions and possible partial unfolding. (2) Exploring the physical and chemical principles of protein binding that govern the protein-protein interactions in the context of the cell. Such principles have to be formulated before one turns to study specificity, affinity, and cross-reactivity. Understanding these global/functional motions of proteins will not only provide an understanding of the biological phenomena but, by learning the function and designing principles of these nanoscale molecular machines, it will lead to a major impact in nanoscience. Using designing principles that mimic these biomolecular machines will allow us to develop an entirely new family of materials, which function at the nanoscale, with applications such as sensing and catalysis.The NSF support has been vital for training students and postdoctoral fellows in the highly interdisciplinary field of molecular biophysics. Besides theoretical training, a strong understanding of the experiments is essential. Five former postdoctoral fellows and two graduate students are now professors at major universities. The PI has always had a good representation of women and members from underrepresented groups in his research.