Project Grant R35GM155222

SUPRAMOLECULAR STRATEGIES TO MODULATE BIOMOLECULAR FOLDING AND ASSEMBLY - PROJECT SUMMARY NATURAL PROCESSES, SUCH AS PROTEIN EXPRESSION, CELL DIFFERENTIATION, AND GENE TRANSCRIPTION, DEPEND ON BIOMOLECULES TO ADOPT SPECIFIC ASSEMBLY STATES AND SECONDARY STRUCTURES, PRIMARILY SHEPHERDED BY NONCOVALENT INTERACTIONS. THESE NONCOVALENT INTERACTIONS ALSO SCAFFOLD THE FORMATION OF MULTICOMPONENT AND THREE-DIMENSIONAL SUPRAMOLECULAR COMPLEXES THAT PROVIDE ACCESS TO ARCHITECTURES WITH (1) LENGTH SCALES MUCH LARGER THAN THEIR INDIVIDUAL COMPONENTS AND (2) DYNAMIC, RECONFIGURABLE STRUCTURES ENABLED BY THE FINITE LIFETIME OF THE NONCOVALENT BOND. HOWEVER, TRADITIONAL THERAPEUTIC AND DIAGNOSTIC INTERVENTIONS FAVOR THE USE OF SMALL MOLECULES WITH FIXED STRUCTURES TO ATTEMPT TO INTERRUPT OR DIRECT THESE NATURAL PROCESSES. WE HYPOTHESIZE THAT, TO FULLY UNDERSTAND, INTERROGATE, AND MODULATE NATURAL PROCESSES, SYNTHETIC CONSTRUCTS WITH SPECIFIC NONCOVALENT INTERACTIONS THAT OPERATE AT LENGTH SCALES AND WITH DYNAMICS COMMENSURATE WITH THEIR NATURAL TARGETS ARE NEEDED. THE OVERARCHING GOAL OF THE PROPOSED RESEARCH IS TO EXPLOIT THE SYNTHETIC POTENTIAL OF SUPRAMOLECULAR CHEMISTRY TO DEVELOP NEW NONCOVALENT MOTIFS AND REACTIONS TO INTERFACE WITH AND INTERVENE IN BIOLOGICAL PROCESSES. IN PURSUIT OF THIS GOAL, ONE RESEARCH DIRECTION IS DEVELOPING SUPRAMOLECULAR MIMICS OF NATURAL CHAPERONES. PROTEIN FOLDING IS A CHAOTIC PROCESS THAT RELIES ON NATURAL CHAPERONES TO MARSHAL PROTEINS TOWARDS THEIR FUNCTIONAL STRUCTURES. WE RECENTLY DISCOVERED A SERIES OF AMPHIPHILIC MOLECULES THAT ASSEMBLE INTO SUPRAMOLECULAR CAPSULES AND INHIBIT THE FIBRILLATION OF AN AMYLOID BETA PROTEIN FRAGMENT. FUTURE WORK IN THIS AREA SEEKS TO CAPITALIZE ON THIS DISCOVERY TO ESTABLISH STRUCTURE-FUNCTION RELATIONSHIPS THAT RELATE MOLECULAR STRUCTURE, ASSEMBLY PROPERTIES, AND CHAPERONE-LIKE FUNCTION, AND ESTABLISH DYNAMIC PHOTOSWITCHES TO MODULATE THE HYDROPHOBICITY OF OUR SUPRAMOLECULAR CHAPERONES IN SITU AND INDUCE PROTEIN REFOLDING. OUR SECOND RESEARCH DIRECTION WILL ESTABLISH NEW RECOGNITION MOTIFS FOR CANONICAL (WATSON-CRICK-FRANKLIN, WCF) AND NON-CANONICAL BASE PAIRS IN NUCLEIC ACIDS. THOUGH MOST BASE-BASE INTERACTIONS IN DNA AND RNA CONSIST OF WCF INTERACTIONS, NON-WCF INTERACTIONS AND MISMATCHED BASE PAIRS ARE IMPORTANT STRUCTURAL FEATURES, IMPLICATED IN DNA CYTOTOXICITY AND RNA FUNCTION. TYPICAL APPROACHES TO TARGET SUCH STRUCTURES RELY ON SMALL MOLECULE INTERCALATORS THAT REQUIRE IDENTIFIABLE BINDING POCKETS. TO CIRCUMVENT THIS LIMITATION, WE ARE DEVELOPING BIFACIAL NUCLEOBASES THAT HARNESS INHERENT BASE-PAIRING TO TARGET SPECIFIC NUCLEIC ACID SEQUENCES AND STRUCTURAL FOLDS. IN SUM, THE PROPOSED RESEARCH PROGRAM WILL ADVANCE FUNDAMENTAL UNDERSTANDING ABOUT THE MOLECULAR RECOGNITION OF BIOMOLECULAR PRIMARY AND SECONDARY STRUCTURES AND ESTABLISH NEW RECOGNITION MOTIFS THAT WILL UNDERPIN THE DEVELOPMENT OF FUTURE DIAGNOSTICS AND THERAPEUTICS.