CHEM 732 Fall 2011: Advances in Macromolecular Structure Two ...

CHEM 732 Fall 2011: Advances in Macromolecular StructureTwo Credit Hours, Tuesday/Thursday, 8:00 – 9:15, Venable G307Instructor, Gary PielakOffice hours: 4:00-5:00 PM Friday in Kenan 748 or by appointment.*Order ACS Style Guide (second edition, eBay ~$5) on day of first lecture.*Download pdf files of the papers cited on page 3 before second lecture.*Begin readings on page 3 before second lecture.*We will discuss the topics described on page 3. Be prepared to take partin discussions and ask questions.Lecture ScheduleTuesday 08-23 Start Topics on page 3. Order ACS Style Guide.Download pdfs. Steady state kinetics of enzymes.Thursday 08-25Standard states and the Eyring equation.Tuesday 08-30 Continue topics on page 3…Thursday 09-01Tuesday 09-06Thursday 09-08Tuesday 09-13Thursday 09-15Tuesday 09-20 How to choose a mentorThursday 09-22How to choose a mentorTuesday 09-27Thursday 09-29Tuesday 10-04 Nobel Prize in Physiology (announced 10-3)Thursday 10-06 Nobel Prize in Chemistry (announced 10-5)Tuesday 10-11

CHEM 732 Syllabus, page 2Thursday 10-13Tuesday 10-18Thursday 10-20no class, fall breakTuesday 10-25Thursday 10-27Pass out take-home examinationGrading. Take home examinations.Exam is due Thursday, November 4, and accounts for 67% of gradeLetter grades are assigned as described below.av is the class average. sd is the standard deviation of the mean.H >[av + (1.75 x sd)]P+ >[av + (1.50 x sd)]P >[av - (0.50 x sd)]L >[av - (1.50 x sd)]F

CHEM 732 Syllabus, page 3Why study enzymes?Topics & ReadingspH and the Henderson-Hasselbalch Equation. Any biochemistry text.Steady State Enzyme KineticsAny biochemistry textbook, but Fersht [(1999). Structure and mechanism inprotein science: a guide to enzyme catalysis and protein folding. NewYork, Freeman] gives a nice overview.Deriving the Michaelis-Menten equationWhat do Km and kcat mean?Standard state free energies. Eyring equation. Any p-chem text.How to Review and Write a Paper: The ACS Style Guide, 2 ndeditionEnzyme ProficiencyWhat is it?Most Proficient Enzyme KnownEnzyme evolution—hypotheses and neo DarwinismLewis CA, Wolfenden R. 2008. Uroporphyrinogen decarboxylation as abenchmark for the catalytic proficiency of enzymes. Proceedings of theNational Academy of Sciences 105: 17328Stockbridge RB, Lewis CA, Yuan Y, Wolfenden R. 2010. Impact of temperatureon the time required for the establishment of primordial biochemistry, andfor the evolution of enzymes. Proceedings of the National Academy ofSciences 107: 22102False Starts at Enzyme DesignAlan Fersht: TrustAltamirano MM, Blackburn JM, Aguayo C, Fersht AR. 2000. Directed evolutionof a new catalytic activity using the α/β-barrel scaffold. Nature 403: 617Altamirano MM, Blackburn JM, Aguayo C, Fersht AR. 2002. retraction:Directed evolution of new catalytic activity using the α/β-barrel scaffold.Nature 417: 468Homme Hellinga: Error analysis & mentor-student interactionsDwyer MA, Looger LL, Hellinga HW. 2004. Computational design of abiologically active enzyme. Science 304: 1967Dwyer MA, Looger LL, Hellinga HW. 2008. Retraction. Science 319: 569Hayden EC. 2008. Chemistry: Designer debacle. Nature 453: 275

CHEM 732 Syllabus, page 4Hellinga HW. 2008. In the wake of two retractions, a request forinvestigation. Nature 454: 397A Successful DesignRöthlisberger D, Khersonsky O, Wollacott AM, Jiang L, DeChancie J, BetkerJ, Gallaher JL, Althoff EA, Zanghellini A, Dym O, Albeck S, Houk KN,Tawfik DS, Baker D. 2008. Kemp elimination catalysts by computationalenzyme design. Nature 453: 190Or Was It?Holfelder F, Kirby AJ, Tawfik DS. 1996. Off-the-shelf proteins that rivaltailor-made antibodies as catalysts. Nature 383: 60Lassila JK, Baker D, Herschlag D. 2010. Origins of catalysis bycomputationally designed retroaldolase enzymes. Proceedings of theNational Academy of Sciences 107: 4937Is there a simpler way to get an enzyme this good?Korendovych IV, Kulp DW, Wu Y, Cheng H, Roder H, DeGrado W F. 2011. Designof a switchable eliminase. Proceedings of the National Academy of Sciences108: 6823.Maybe the best was done years agoAbrahmsen L, Tom J, Burnier J, Butcher KA, Kossiakoff A, Wells JA. 1991.Engineering subtilisin and its substrates for efficient ligation ofpeptide bonds in aqueous solution. Biochemistry 30: 4151What makes a good drug? Lipinski rules of fiveLipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental andcomputational approaches to estimate solubility and permeability in drugdiscovery and development settings. Advanced Drug Delivery Reviews 1997;23: 3-25.