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SUMMARY:Exploring the free energy surface of proteins using CEST NMR exper
 iments - Dr Pramodh Vallurupalli (TIFR Hyderabad)
DTSTART;VALUE=DATE-TIME:20231212T150000Z
DTEND;VALUE=DATE-TIME:20231212T160000Z
UID:https://talks.ox.ac.uk/talks/id/62eeb40e-44f6-4bfe-b054-09ca39642bd3/
DESCRIPTION:Protein molecules interconvert between multiple conformational
  states that can play important roles in their function\, misfunction and 
 folding. Often these states are invisible to traditional biophysical metho
 ds as they are sparsely populated. The Chemical Exchange Saturation Transf
 er (CEST) NMR experiment that was originally conceived 60 years ago [1] wa
 s only relatively recently adapted to study sparsely populated states in p
 roteins [2]. In this talk I will present a recent development that conside
 rably extends the ability of the CEST experiment to probe exchange between
  multiple states over a range of timescales and show that it now becomes p
 ossible to detect invisible states with extremely low populations (~0.1%) 
 and a wide range of lifetimes (~10-5 to ~10-1 s) [3]. Using this strategy 
 we discovered that the small 71 residue A39G FF domain folds from the unfo
 lded (U) to the folded (F) state via two pathways involving two intermedia
 tes (I1 and I2) on a volcano shaped free energy surface [3]. The structure
  of the I1 state was determined almost a decade ago using CPMG experiments
  [4] and we have now used CEST experiments to determine the structure of t
 he newly discovered I2 state that turns out to be more compact than the I1
  state. Urea m-values of the different states (U\, I1 and I2) and the tran
 sition states that separate them have also been determined. The structures
  of the two folding intermediates along with the thermodynamic parameters 
 provide unprecedented insights into the folding mechanism of the small FF 
 domain. I will all also present recent developments with the CEST methodol
 ogy that makes it ‘straight-forward’ to study three-state exchange on 
 occurring on the millisecond time-scale thus detecting states missed by CP
 MG [5]. An extension of CEST to study exchange occurring at ~104 s-1 will 
 be also be discussed [6].\n[1]J Chem Phys\, 1963. 39(11): p. 2892-2901.\n[
 2]J Am Chem Soc\, 2012. 134(19): p. 8148-61.\n[3]Proc Natl Acad Sci U S A\
 , 2021. 118(46): e2115113118 [4]Science\, 2010. 329(5997): p. 1312-1316\n[
 5]J Biomol NMR (in press)\n[6]J Biomol NMR\, 2023. 77: p. 165–181\nSpeak
 ers:\nDr Pramodh Vallurupalli (TIFR Hyderabad)
LOCATION:Dorothy Crowfoot Hodgkin Building (Biochemistry Phase 1 seminar r
 oom)\, off South Parks Road OX1 3QU
TZID:Europe/London
URL:https://talks.ox.ac.uk/talks/id/62eeb40e-44f6-4bfe-b054-09ca39642bd3/
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DESCRIPTION:Talk:Exploring the free energy surface of proteins using CEST 
 NMR experiments - Dr Pramodh Vallurupalli (TIFR Hyderabad)
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