Basic Rules of Protein Folding Seth Lichter Northwestern University - - PowerPoint PPT Presentation

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Basic Rules of Protein Folding Seth Lichter Northwestern University - - PowerPoint PPT Presentation

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Basic Rules of Protein Folding Seth Lichter Northwestern University Mechanical Engineering Dept. 1 Basic Rules of Protein Folding Pengfei Diao Ashlie Martini Seth Lichter 2 3 4 5 6 7 8 9 10 http://www.thecephalopodpage.org/ 11 12

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Seth Lichter Northwestern University Mechanical Engineering Dept.

Basic Rules of Protein Folding

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Basic Rules of Protein Folding

Seth Lichter Ashlie Martini Pengfei Diao

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http://www.thecephalopodpage.org/

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H.-Y. Wang, UCSC

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Kinosita Lab

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Kinosita Lab

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Junge Lab

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Jmol

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Jmol

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Jmol

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Jmol

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alpha helix beta sheet

  • C. Bearden, Rice University
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Hydrogen bonds in alpha helices

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Hydrogen bonds in beta sheets

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  • M. Farabee, Estrella Mountain Community College

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  • M. Farabee, Estrella Mountain Community College

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Protein synthesis

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The protein folding problem

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How do proteins fold?

Given the amino acid sequence, predict the protein’s three-dimensional structure.

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Methods of study Molecular Dynamics simulations: All atom Ab initio

  • ther…

Minimalistic models: Go Lattice

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The protein folding problem

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  • S. Kmiecik and A. Kolinski, Biophys. J. (2007)

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time

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g

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OK, interesting. Importance?

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S.S. Sisodia & P.H. St George-Hyslop Nature Rev. Neurosci. (2002)

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Misfolding leading to Alzheimer’s disease

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g

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A.J. Berk Oncogene (2005)

Folding and misfolding mechanisms of the p53 DNA binding domain at physiological temperature

JAMES S. BUTLER AND STEWART N. LOH Protein Science (2006), 15:2457-2465

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temperature

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OK, interesting. Importance?

Understanding and treating disease

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Why Mechanical Engineers?

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Sieve pump

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Flow meter

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Given the amino acid sequence, predict the protein’s three-dimensional structure.

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Methods of study—Experimental Atomic force microscope Laser tweezers

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  • C. Cecconi et al. Science (2005)

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folded unfolded

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  • C. Cecconi et al. Science (2005)

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folded unfolded

How can the Force vs. Extension curves during folding be predicted?

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Two-state model

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Rate of unfolding

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Rate of folding

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Unfolding & folding rates for F = 0

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Rate of unfolding with Force

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F F

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Rate of folding with Force

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F F

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Folding times

Fernandez & Li, Science (2005)

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Unfolding Folding

Individual Bond (IB) Model

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Unfolding Folding

Individual Bond (IB) Model

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Unfolding Folding

Individual Bond (IB) Model

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Individual Bond (IB) Model

  • 1. Independent rate rule

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Individual Bond (IB) Model

  • 1. Independent rate rule
  • 2. Exterior length rule

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Individual Bond (IB) Model

  • 1. Independent rate rule
  • 2. Exterior length rule
  • 3. Interior force rule

F = 0

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Unfolding Folding

Individual Bond (IB) Model

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  • 1. Independent rate rule
  • 2. Exterior length rule
  • 3. Interior force rule
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  • C. Ceconi et al. Science (2005)

just the tether tether + protein

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just the tether tether + protein Experiments (Cecconi et al.) Individual Bond Model

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23 24 25 26 27 28 29 30 31 32 23 24 25 26 27 3 2 31 30 29 28 Sequence distance = 6 4 2 94 9 5 9 6 9 7 9 8

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Folded protein:

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5 9 5

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At zero force…

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5 9 5 5 9 5

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At zero force…

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5 9 5 5 9 5

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At zero force…

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5 9 5 F F

Xf

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For Force = 0

5 9 5

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5 9 5 2 4 1 6 78 8 3 F F

Xf Xf Xf

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For Force = 0

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5 9 5 2 4 1 6 7 8 8 3 F F

Xf Xf

16 2 4 7 8 8 3 9 5 5

Xf Xf

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For Force = 0

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5 9 5 2 4 1 6 78 8 3 F F

Xf Xf

16 2 4 78 8 3 9 5 5

Xf Xf

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For Force = 0

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~ Xf

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Experiment (ubiquitin, Fernandez & Li) Individual Bond Model Two-state model

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Individual Bond (IB) Model

Results: Folding times Extension vs. force

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Individual Bond (IB) Model

Results: The effect of force on the folding pathway

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Proteins are complex mechanisms, which fold into different types of structural elements and machines. Proteins self assemble. Errors in self-assembly lead to disease. Understanding protein folding can lead to: therapies… nanoscale devices.

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Protein folding is not understood. The two-state model does not fit with observation. New minimalistic models help us understand folding. The IB Model shows that features of folding are due to simple one-dimensional rules:

  • 1. Independent rate rule
  • 2. Exterior length rule
  • 3. Interior force rule

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Folding times Extension vs. force Folding pathway

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Questions & Answers

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Protein Data Bank