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Understanding Protein Dynamics: Binding, Transformation, and Release Mechanisms

This lecture delves into the intricate dynamics of protein structure, focusing on the processes of binding, transformation, and release. It covers various protein motifs such as Zn-fingers, leucine zippers, and immunoglobulin folds that play a crucial role in DNA and RNA binding. The discussion encompasses catalytic mechanisms, including the stabilization of transition states, the role of rigid enzymes, and the significance of post-translational modifications. By exploring enzyme kinetics, interactions, and protein engineering, participants will gain insights into the functional versatility of proteins in biological systems.

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Understanding Protein Dynamics: Binding, Transformation, and Release Mechanisms

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  1. PROTEIN PHYSICS LECTURE 24-25 PROTEIN STRUCTURE AT ACTION: BIND  TRANSFORM  RELEASE

  2. BIND: repressors -turn-

  3. Zn- fingers DNA & RNA BINDING Leu-zipper

  4. BIND  RELEASE:REPRESSOR -BINDING-INDUCED DEFORMATION MAKES REPRESSOR ACTIVE, and IT BINDS TO DNA

  5. Immunoglobulin

  6. Standard positions of active sites in protein folds

  7. There are some with catalytic (Ser-protease) site

  8. BIND TRANSFORM RELEASE Catalysis: stabilization of the transition state (TS) Theory: Pauling & Holden Preferential binding of TS: RIGID enzyme

  9. Catalysis: stabilization of the transition state (TS) Theory: Pauling & Holden Experimental verification: Fersht reputed TS __________ ______ P

  10. Catalysis: stabilization of the transition state (TS) Theory: Pauling & Holden Experimental verification: Fersht / This protein engineering reduces the rate by 1000000 / / / reputed TS __________ ______ P Preferential binding of TS: RIGID enzyme

  11. BIND TRANSFORM RELEASE Catalytic antibodies ABZYM = AntyBodyenZYM Transition state (TS) Preferential binding of TS: RIGID enzyme Antibodies are selected to TS-like molecule

  12. BIND TRANSFORM  RELEASE:ENZYME chymotrypsin Note: small active site

  13. Sometimes: Different folds with the same active site: the same biochemical function

  14. POST-TRANSLATIONAL MODIFICATION Sometimes, only theCHAIN CUT-INDUCED DEFORMATION MAKES THE ENZYME ACTIVE READY  non-active “cat. site” active cat. site CUT Chymotripsinogen Chymotripsin

  15. Chymotrypsin catalyses hydrolysis of a peptide Spontaneous hydrolysis: very slow

  16. SER-protease: catalysis

  17. CHYMOTRYPSIN ACTIVE SITE with INHIBITOR

  18. Preferential binding of TS: RIGID enzyme F = k1x1= - k2x2 Ei = (ki/2)(xi)2 = F2/(2ki) Hooke’s & 2-nd Newton’s Energy is concentrated laws in the softer body. Effective catalysis: when substrate is softer than protein Kinetic energy cannot be stored for catalysis Friction stops a molecule within picoseconds: m(dv/dt) = -(3D)v [Stokes law] D – diameter; m ~ D3 – mass;  – viscosity tkinet 10-13 sec  (D/nm)2in water

  19. PROTEIN STRUCTURE AT ACTION: BIND  TRANSFORM  RELEASE RIGID CATALITIC SITE INDEPENDENT ON OVERALL CHAIN FOLD

  20. MOTIONS

  21. Double sieve: movement of substrate from one active site to another  tRNAIle

  22. Movement in two-domain enzyme: One conformation for binding (and release), another for catalysis

  23. Two-domain dehydrogenases: Universal NAD-binding domain; Individual substrate-binding domain

  24. Movement in quaternary structure: Hemoglobin vs. myoglobin

  25. МиозинАктин АТФ  АДФ + Ф 15 ккал/моль в клеточных условиях Механохимический цикл

  26. Myosin Actin Mechanochemical cycle

  27. SUMMARY

  28. PROTEIN PHYSICS • Interactions • Structures • Selection • States & transitions

  29. Intermediates & nuclei • Structure prediction & bioinformatics • Protein engineering & design • Functioning

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