Measurable Physics of the Transition State Ensemble in Protein Folding .


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Statistical Physics of the Transition State Ensemble in Protein Folding . Alfonso Ramon Lam Ng, Jose M. Borreguero, Feng Ding, Sergey V. Buldyrev, Eugene Shakhnovich and H. Eugene Stanley 2004. The Protein Folding Problem. At the Protein Folding Temperature T F:.
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Slide 1

Factual Physics of the Transition State Ensemble in Protein Folding Alfonso Ramon Lam Ng, Jose M. Borreguero, Feng Ding, Sergey V. Buldyrev, Eugene Shakhnovich and H. Eugene Stanley 2004

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The Protein Folding Problem At the Protein Folding Temperature T F: Protein Folding Process Intermediate States Folded Unfolded Transition State Ensemble (TSE) What is TSE? Set of Protein Conformations situated at the highest point of the free vitality hindrance that has similar likelihood to crease or unfurl . ( Du et al.,1998 ) Unfolded Folded

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Characterize the structure of the TSE at the amino corrosive level. Reason: Provide a direction for amino corrosive substitution in experiments.(*) Why?: Our Results: 1.- The computed TSE concurs with exploratory information . 2.- The TSE can be isolated into a discrete arrangement of collapsing pathways. (*): Martinez and Serrano, Nature Structural Biology,1999. Puzzle et al, Nature ,1999, Gsponer et al, PNAS,2002, Vendruscolo et al, Biophysical Journal.,2003

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Our Protein: SH3 1.- Small Protein: 56 amino acids. 2.- Folds rapidly. 3.- Well concentrated on by investigations. (*) (*) Riddle et al, Nature ,1999. Martinez and Serrano, Nature Struct. Bio.,1999.

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1 Amino Acid The Two-Bead Representation From its nuclear structure to a coarse grained show

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The Two-Bead Model Effective Bonds C  - C  and C  - C  Interactions: Covalent Bonds r Backbone Feng Ding et al., Biophysical Journal,2001

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- 1 b) C  - C  Interactions: Native Contact Map 7.5 Å : Native contact between amino acids Cutoff = 7.5 Å

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Obtaining the TSE Run Long Time DMD Simulation at T F =0.91. Select the Potential Energy as the surmised Path of Reaction. Vitality window between - 90 and - 80 to find the TSE (*). Record adaptations inside the vitality window . Unfurled - 55 - 80 - 90 TSE Folded - 122 5200 Candidate Conformations got. (*) Feng Ding et al., Biophysical Journal,2001

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Filtering the TSE Candidates Calculating Folding Probability P F 1.- TSE compliance has P F ~ 0.5. 2.- Run N keeps running of DMD reproductions for every competitor adaptation at T = 0.91. 3.- Calculate P F with: P F = N Folded/N runs 1525 Members of TSE acquired out of 5200 applicants. Case : N runs = 4 , P F = 2/4 =1/2 N Folded = 2 E Unfolded - 55 1 3 - 80 - 90 2 4 - 122 Folded TIME

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Frequency 8 1 0 6(*) (*) (*) (*) Amino Acid Index 5 7(*) 4 3 2(*) 1 Amino Acid Index The TSE Average Contact Map (*) : Martinez and Serrano, Nature Structural Biology,1999

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z y x Root Mean Square Distance (rmsd) 1.- Take two protein compliances C1 and C2 and superpose the focuses of mass. C1 C2 2.- Find the revolution that minimizes the capacity:

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c1 c2 c3 c4 c5 c1 c3 c4 c2 c5 c1 c2 c5 c3 c4 . . . Until acquired 1 bunch of 5 individuals The Clustering Algorithm(*) 1.- Find combine of groups with negligible root mean square separation (rmsd). 2.- Join them. Go to next stage and rehash system. (*): Sneath,P.H.A., Numerical Taxonomy,1973

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Clustering Tree TSE 1 2 A 3 4 5(*) A B (*)Two comparable Folding Pathways when we have 5 Clusters.

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The Clusters Set of TSE for T=0.91 The TSE can be partitioned into a discrete arrangement of Folding Pathways

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Changing Pathways Preferences 1.- Increase the power of contacts for bunch 4 and decrease the force of contacts for group 1 by utilizing E\' = E(1- ). 2.- The new compliances are utilized as beginning stage as a part of our examination. 3.- Repeat all means to get the TSE individuals and make bunching. Comes about: most of the compliances changes their pathways

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Summary TSE structure can be depicted through a limited number of collapsing pathways. The inclination of a compliance to take after a collapsing pathway can be controlled by changing the power of the contacts exhibit in a pathway.

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Discrete Molecular Dynamics (DMD) t ij Two particles moves with speeds v i and v j with relative position r ij . v i v j i When separation between these two particles gets to be R ij , an impact happens and the crash time t ij fulfills: (r ij + t ij v ij ) 2 = R ij 2 R ij j Select the combine with least t ij and rehash. These amounts are monitored: E i + E j , P i + P j and L i + L j

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Why 4 Clusters? 4 Clusters Two comparative Folding Pathways when we have 5 Clusters.

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48.4% 57.4% 17.2% Unfolded State Temperature 0.86 7.60% 40.5% 3.50% 0.91 9.42% 29.7% 3.48% 0.95 11.8% 42.0% 29.0% Folded State

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