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DTSTART;TZID=America/Los_Angeles:20210506T120000
DTEND;TZID=America/Los_Angeles:20210506T120000
DTSTAMP:20260618T132050
CREATED:20210331T172442Z
LAST-MODIFIED:20210331T172442Z
UID:13482-1620302400-1620302400@www.chemistry.ucla.edu
SUMMARY:Chem 218 Student Exit Seminar: Jack Fuller
DESCRIPTION:Secondary Coordination Effects in Artificial Biotin-Streptavidin Metalloenzymes \n Designing artificial metalloenzymes is of interest because they combine the catalytic activity of possibly non-physiological but highly catalytically potent metals and the selectivity and mild operational conditions enabled by the protein. This talk will focus on joint theory-experiment efforts to design Rh and Ir artificial metalloenzymes\, catalyzing the formation of 5-membered and 6-membered N-heterocycles. The biotin-streptavidin system has been used as a relatively simple and robust platform to create metalloenzymes by embedding organometallic catalysts in the protein. The monomeric streptavidin is known to retain the fold upon many different mutations\, thus enabling the control over the second coordination sphere of the metal and fine-tuning of the metal electronic properties in a variety of ways without losing the entire structure. Biotin-Sav artificial metalloenzymes prepared in this way and containing Rh/Ir(Cp*) have shown improved reactivity and selectivity over simpler organometallic catalysts. We aimed to both explain the improved activity and to enhance it further by strategic mutagenesis. We have analyzed the secondary coordination effects using quantum mechanistic calculations\, bonding analysis\, and hybrid quantum mechanical/molecular mechanical simulations. In collaboration with experiment\, we probed a library of mutants. In particular\, we show that the pi-pi interaction between the catalyst and a tyrosine sidechain decreases rate-determining barriers. Additional residues in the vicinity of Tyr contribute to the quality of the pi-pi contact and the reactivity tuning. More remote mutations within the protein scaffold affect the protein structure and dynamics slightly\, and thus affect the pi-pi contact indirectly\, also impacting the activity. Successful and failed strategic and accidental mutations were made with the goal of improving the pi-pi contact\, and will be discussed. Finally\, we demonstrated that the activity correlates the most with the properties of the ensemble of states within the protein dynamics\, showcasing the need for rapid QM/MM sampling in this work.
URL:https://www.chemistry.ucla.edu/seminars/chem-218-student-exit-seminar-jack-fuller/
CATEGORIES:Other,Seminars
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DTSTART;TZID=America/Los_Angeles:20210506T160000
DTEND;TZID=America/Los_Angeles:20210506T160000
DTSTAMP:20260618T132050
CREATED:20210329T185010Z
LAST-MODIFIED:20210329T185010Z
UID:13479-1620316800-1620316800@www.chemistry.ucla.edu
SUMMARY:Strain molecules assist peptide and protein synthesis\, a new venue for thiolactones
DESCRIPTION: Abstract: The broad application of macrocycles has illustrated significant potential as therapeutic agents. 12-membered ring cyclotetrapeptides are particularly attractive entities among all the cyclic peptides. Compared with macrocycles of larger ring size\, the characteristic head-to-tail or end-to-end peptidyl backbone provides intrusive structural motif of circular peptides grants distinct biological properties such as resistance to degradation\, enhanced conformational stability\, and increased epitope interactions with other biomolecules. Ability to acquire a sufficient quantity of high purity of cyclo-tetrapeptide could significantly promote their chemical and biological studies. \nIt is worth noting that the traditional coupling methods to achieve chemical synthesis of macrocycles have been a formidable challenge\, requiring fully protected linear precursors and harsh conditions to achieve activation of the C-terminal residue for the cyclization. The harsh activation conditions are required to overcome the entropy barrier during the coupling often lead to epimerization of the C-terminal amino acid residue and peptide oligomerization. The practical strategy to attain macrocycles with a consensus sequence of L-cyclo(Pro-Xxx-Pro-Xxx)\, where Xxx = Val\, Tyr\, Leu\, Phe\, are elusive. There is the urgent need to develop a strategy to prepare circular tetrapeptides. Based on our previously reported β-thiolactone mediated chemistry\, iii we were able to construct tetra-cyclic peptides in high yields. The strategy could be applied to produce a broad number of all-L-cyclo-tetrapeptides and the reactions were performed at room temperature in the aqueous buffer. The β-thiolactone furnished cyclization protocol prevented the amino acid epimerization during the cyclization and proved as a powerful general strategy for cyclic peptide synthesis.
URL:https://www.chemistry.ucla.edu/seminars/strain-molecules-assist-peptide-and-protein-synthesis-new-venue-thiolactones/
CATEGORIES:Organic Colloquium,Seminars
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