Kinetic Proofreading


Richard Neher
Biozentrum, University of Basel


slides at neherlab.org/20180924_computational_system_biology_hopfield.html

Why be accurate?

  • Much of biology relies on error free synthesis of very long polymers (DNA, proteins)
  • If the per base/aa error rate is $\epsilon$, probability of an error free product is $e^{-\epsilon L}$
  • Error free replication of a bacterial chromosome ($10^7$ bases) requires error rates $\ll 10^{-7}$

Error rates of genome replication

Sanjuan et al. 10.1126/science.1169202
John Hopfield
Princeton University
Jaques Ninio
ENS Paris

Self/non-self antigen discrimination by T-cells

  • T-cells scan MHC/peptide complexes for evidence infection.
  • Many self-antigens, few non-self.
  • Interactions energies are similar.
  • Need for rapid but accurate discrimination.
T cell receptor binding to MHC-antigen complex. Courtesy of J. Kimball
T-cells are activated via a phosphorylation cascade that implements kinetic proof reading

What limits accuracy?

Michaelis-Menten reaction

$S + E \leftrightharpoons ES \rightarrow P + E $
  • Biochemical reactions typically go through intermediate states.
  • On rates are similar, limited by diffusion.
  • Discrimination is via the off-rates
  • Off-rates determine the life time of the intermediate.
  • Off-rates are determined by the free energy of the transition state
  • The ratio of off-rates is given by $e^{-\Delta G/kT}$. Lower limit for error rate!
  • Typical energies of discrimination are low.
  • DNA base pairing/stacking energies $\sim 3kT$
  • Translation is based on mRNA/anti-codon interaction. Mismatches cost a few $kT$.