William Marsh Rice University

The Energy Landscape for Folding and Function of Biomolecules: From Proteins to Chromatin -this Project Focuses on Developing Models to Explore Chromatin Structure and Dynamics, and Protein Complex Assembly. Chromatin Is the Material of Which the Chromosomes of Organisms Other Than Bacteria Are Composed. This Project Will Create Computational Models Needed to Investigate the Genome Organization in Different Species and Phases of the Cell Cycle. at the Biomolecular Level, This Project Will Integrate Structural Models and Computer Simulations to Understand Structure, Dynamics, and Function of Large Biomolecular Complexes, Like Chromatin. Broader Impacts of This Project Include the Development of Publicly Available Software/web-servers for Protein and Chromatin Folding, Dynamics, and Function. Emphasis Is Also Given to Training, Particularly of Students From Underrepresented Groups. to Achieve the Project Goals, Models Will Be Developed to Explore Chromatin Structure and Dynamics and Protein Complex Assembly. in the Genome Architecture Research, the Minimal Chromatin Model (michrom) Will Be Expanded to Determine New Parameters Necessary to Accommodate Several Different Species. Going Beyond the Current Parameters That Have Been Optimized for Chromosomes at the Interphase, New Parameters Will Be Needed to Explore Chromosome Structural Ensembles Across the Cell Cycle, Going From the Interphase Through the Metaphase. Predictions of These Models Will Be Validated Against Microscopy Data. Also, Full Nucleus Simulations Will Investigate Chromosome Ensembles in the Context of All Other Chromosomes and Also the Influence of Nuclear Lamina-chromatin Interactions. the Current Chromatin Model Will Be Generalized to Go Beyond Just a Few Types and Subtypes and Predict These Chromosome 3D Structural Ensembles With a Completely General Energy Function; a Direct Inversion of Hi-c Data. Such Generalization Will Be Needed to Understand Features That Are Not Currently Considered by Standard Michrom and to Investigate Genomes of Species That Show Little Compartment Formation on Their Chromosomal Structures. the Second Aspect of This Project Will Be on the Investigation of Large Protein Complexes Using a Combination of Structure-based Models (SBM) and Direct Coupling Analysis (DCA) to Predict Their Global Structural and Functional Landscape. These Results Will Be Integrated With Physical Simulations That Are Needed to Understand Detailed Energetics of Local Structural Conformations and Quantitative Predictions of the Transitions Between These Conformations. Although the Research Will Focus on Structural Maintenance Chromosome (SMC) Protein Complexes and the Spyke Protein in SARS-COV-2, This Strategy May Also Be Applied to Several Other Large Biomolecular Systems. This Project Is Funded by the Physics of Living Systems in the Division of Physics and the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences. 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.