Exploring the Protein Funnel Energy Landscape for Folding

Exploring the Protein Funnel Energy Landscape for Folding and Function Jos N. Onuchic Workshop III - Structural Proteomics IPAM - UCLA Los Angeles, May 2004 Center for Theoretical Biological Physics UCSD ctbp.ucsd.edu

Energy Landscape Idea Rough Landscape Random Heteropolymer Frustration!! Try to minimize frustration! Tf Stability Tg Roughness Stability Gap

Proteins Principle of Minimal Frustration (Bryngelson/Wolynes, Go) Realization of Minimal Frustration in Funnels Go-model Tf/Tg=1.6 Tf/Tg=1.3

H. Nymeyer, N. Socci and J.Onuchic, PNAS 2000 C.Clementi, H.Nymeyer, J.Onuchic, JMB 2000 Go-like potential = only native interactions are taken into account (named after a paper by Taketomi, Ueda, Go 1975) 2 2 Analysis of two-state folders:

Transition State structure for CI2 and SH3 Probability of contact formation at TS distal loop SH3 Diverging turn CI2 These descriptions are in good agreement with experimental results (Jackson & Fersht 1991, Grantcharova C.Clementi, H.Nymeyer, J.Onuchic, JMB 2000

et al. 1998). Analysis of proteins which fold through the formation of an intermediate: results for Barnase, RnaseH, CheY Barnase Rnase H CheY A local minimum in the free energy profile between the unfolded and folded minima locates a folding

intermediate state. H.Nymeyer, J.Onuchic, JMB 2000 C.Clementi, CheY In agreement with experimental results (LopezHernandez & Serrano, 1996) we found that in the ``misfolded" structure, all the five -heliceshelices are rather structured, while in the later occurring transition How about water effects?

r* Desolvation models: Hummer, G., et al, PNAS 1997 M. Cheung, A. Garcia and J.Onuchic, PNAS 2002 Tf M. Cheung, A. Garcia and J.Onuchic, PNAS 2002 What are the folding routes for SH3?

Why this kind of mutation? Alanine Valine Q Val la A

Multiple -value analysisvalue analysis Energy Landscape Theory Pse ud Va l with Luis Serrano oQ Th

r Threonine A kinetic analysis on SH3 mutants using LJ and Desolvation potentials Using a desolvation potential, V44T and V53T show dramatic changes in folding time! 9 46 44

58 53 23 Although V44T and V53T show a dramatic decrease in folding rates, the nature of their kinetic traps are different. By going through alternate rounds of theoretical analysis and experimental development, we are revealing the mechanism of protein folding progressively!

RG Q J. Shea, J. Onuchic and C. Brooks III, 2002 Protein A - Distribution of Values N() Helix I-III Turn/Helix I-II

Turn II-III J. Shea, J. Onuchic and C. Brooks, PNAS 1999 Rmsd(A) vs. Native contacts: T~ T* Folded state divided into two basins: Folded solvated Folded desolvated with Angel Garcia

Replica Exchange Sample Trajectories with Angel Garcia The Nature of the landscape Backbone Hydration G (minimal path) 5.5 Free energy

5 4.5 4 3.5 0 Helix formation 0.2 0.4

0.6 0.8 1 H (minimal path) 10 Enthalpy 5 0

-5 - 10 0 T=Tf 0.2 0.4 0.6 0.8 Q Energies in Kcal/mol Collaborators Postdocs:

Osamu Miyashita Koby Levy Antitsa Stoycheva John Finke Yoko Suzuki Shachi Gosavi Cecilia Clementi Rice Joan-Emma Shea UCSB Steve Plotkin UBC Nick Socci Albert Einstein Other Research Groups Peter Wolynes UCSD

Angel Garcia - LANL Pat Jennings UCSD Charles Brooks TSRI Zan Luthey-Schulten UIUC Vitor Leite and Jorge Chahine - Brazil Yoshitaka Tanimura - Kyoto, Japan Yuko Okamoto IMS, Japan Ulrich Hansmann Michigan Tech Chigusa Kobayashi - Kobe, Japan Eric Nelson Texas Students

Leslie Chaves Sichun Yang Margaret Cheung - Maryland Hugh Nymeyer LANL Peter Leopold Funnel Idea -1992 Supported by the National Science Foundation and the Burroughs Wellcome Fund

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