Molecular dynamics of mismatch detection-How MutS uses indirect readout to find errors in DNA.
Biophys J
; 122(15): 3031-3043, 2023 08 08.
Article
in En
| MEDLINE
| ID: mdl-37329136
ABSTRACT
The mismatch repair protein MutS safeguards genomic integrity by finding and initiating repair of basepairing errors in DNA. Single-molecule studies show MutS diffusing on DNA, presumably scanning for mispaired/unpaired bases, and crystal structures show a characteristic "mismatch-recognition" complex with DNA enclosed within MutS and kinked at the site of error. But how MutS goes from scanning thousands of Watson-Crick basepairs to recognizing rare mismatches remains unanswered, largely because atomic-resolution data on the search process are lacking. Here, 10 µs all-atom molecular dynamics simulations of Thermus aquaticus MutS bound to homoduplex DNA and T-bulge DNA illuminate the structural dynamics underlying the search mechanism. MutS-DNA interactions constitute a multistep mechanism to check DNA over two helical turns for its 1) shape, through contacts with the sugar-phosphate backbone, 2) conformational flexibility, through bending/unbending engineered by large-scale motions of the clamp domain, and 3) local deformability, through basepair destabilizing contacts. Thus, MutS can localize a potential target by indirect readout due to lower energetic costs of bending mismatched DNA and identify a site that distorts easily due to weaker base stacking and pairing as a mismatch. The MutS signature Phe-X-Glu motif can then lock in the mismatch-recognition complex to initiate repair.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Escherichia coli Proteins
/
Molecular Dynamics Simulation
Type of study:
Diagnostic_studies
/
Prognostic_studies
Language:
En
Journal:
Biophys J
Year:
2023
Document type:
Article