title: Mechanism for verification of mismatched and homoduplex DNAs by nucleotides-bound MutS analyzed by molecular dynamics simulations.
abstract: In order to understand how MutS recognizes mismatched DNA and induces the reaction of DNA repair using ATP, the dynamics of the complexes of MutS (bound to the ADP and ATP nucleotides, or not) and DNA (with mismatched and matched base-pairs) were investigated using molecular dynamics simulations. As for DNA, the structure of the base-pairs of the homoduplex DNA which interacted with the DNA recognition site of MutS was intermittently disturbed, indicating that the homoduplex DNA was unstable. As for MutS, the disordered loops in the ATPase domains, which are considered to be necessary for the induction of DNA repair, were close to (away from) the nucleotide-binding sites in the ATPase domains when the nucleotides were (not) bound to MutS. This indicates that the ATPase domains changed their structural stability upon ATP binding using the disordered loop. Conformational analysis by principal component analysis showed that the nucleotide binding changed modes which have structurally solid ATPase domains and the large bending motion of the DNA from higher to lower frequencies. In the MutS-mismatched DNA complex bound to two nucleotides, the bending motion of the DNA at low frequency modes may play a role in triggering the formation of the sliding clamp for the following DNA-repair reaction step. Moreover, MM-PBSA/GBSA showed that the MutS-homoduplex DNA complex bound to two nucleotides was unstable because of the unfavorable interactions between MutS and DNA. This would trigger the ATP hydrolysis or separation of MutS and DNA to continue searching for mismatch base-pairs. Proteins 2016; 84:1287-1303. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Quantum Beam Science Research Directorate, National Institutes for Quantum and Radiological Science and Technology, 8-1-7 Umemidai Kizugawa-Shi, Kyoto, 619-0215, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ishida
authors.affiliation: Quantum Beam Science Research Directorate, National Institutes for Quantum and Radiological Science and Technology, 8-1-7 Umemidai Kizugawa-Shi, Kyoto, 619-0215, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsumoto
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D020137:Base Pair Mismatch; D020029:Base Pairing; D001665:Binding Sites; D053843:DNA Mismatch Repair; D004269:DNA, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D056004:Molecular Dynamics Simulation; D051719:MutS DNA Mismatch-Binding Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D059372:Nucleotide Motifs; D025341:Principal Component Analysis; D011485:Protein Binding; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D004269:DNA, Bacterial; D011994:Recombinant Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D051719:MutS DNA Mismatch-Binding Protein
keywords: DNA mismatch repair protein; MM-PBSA/GBSA; base-pair Opening parameter; bending motion of DNA; disordered loops; dynamic domains; free-energy decomposition; principal component analysis (PCA); relative binding free-energy