Evolutionary Covariance Combined with Molecular Dynamics Predicts a Framework for Allostery in the MutS DNA Mismatch Repair Protein

Mismatch
repair (MMR) is an essential, evolutionarily conserved
pathway that maintains genome stability by correcting base-pairing
errors in DNA. Here we examine the sequence and structure of MutS
MMR protein to decipher the amino acid framework underlying its two
key activitiesrecognizing mismatches in DNA and using ATP
to initiate repair. Statistical coupling analysis (SCA) identified
a network (sector) of coevolved amino acids in the MutS protein family.
The potential functional significance of this SCA sector was assessed
by performing molecular dynamics (MD) simulations for alanine mutants
of the top 5% of 160 residues in the distribution, and control nonsector
residues. The effects on three independent metrics were monitored:
(i) MutS domain conformational dynamics, (ii) hydrogen bonding between
MutS and DNA/ATP, and (iii) relative ATP binding free energy. Each
measure revealed that sector residues contribute more substantively
to MutS structure–function than nonsector residues. Notably,
sector mutations disrupted MutS contacts with DNA and/or ATP from
a distance via contiguous pathways and correlated motions, supporting
the idea that SCA can identify amino acid networks underlying allosteric
communication. The combined SCA/MD approach yielded novel, experimentally
testable hypotheses for unknown roles of many residues distributed
across MutS, including some implicated in Lynch cancer syndrome.