Deficiency of the MutSbeta protein has been proven to be a cause of Lynch Syndrome, also known as hereditary non – polyposis colorectal cancer (HNPCC), that leads to hereditary colorectal (colon) cancer. It is known that the absence of this protein or the energy source thereof would result in a failure to detect the DNA base pairing errors, inhibiting the signaling for the mismatch repair pathway to proceed. To examine the essential role of MutSbeta and to understand the nature of the interface between MutSbeta and a mismatched DNA strand at the onset of detection, three sets of molecular dynamics (MD) simulations are performed on the MutSbeta and mismatched DNA controls and on a system containing MutSbeta and mismatched DNA complex. Interactions at the onset of detection are analyzed and the stability of the complex was quantified through examination of root – mean square deviation (RMSD), hydrogen bonds, salt bridges, center of mass, secondary structure of MutSbeta and non-bonding energies at the interface of the complex as the MutSbeta scanned the DNA strand for the missing base. In the first 100 ns, the outermost domain of MutSbeta (clamp P4 on chain B) holds the DNA, and the trajectory indicates that the inner domains (P1 on chains A and B) prepare to scan the DNA strand, a process that continues for the next 100ns. RMSD of 5-7Å for the control MutSbeta compared to the one in the presence of the mismatched DNA of 3-6.5Å, number of salt bridges and the center of mass analysis indicate that starting ~75ns, the MutSbeta initiates the scanning of the mismatched DNA as evidenced by the reduction in the distance between the center of masses of the two by 16Å. The non – bonding energies in terms of Van der Waals show increased attraction of 25 kCal/mol starting ~86ns, which continues to increase further up to ~40 kCal/mol. This along with electrostatic energy analysis also demonstrated the role of positive and hydrophobic residues of MutSbeta in the detection process.

Understanding the interactions between a human mismatch repair protein, MutSbeta and a mismatched DNA

ACS Spring Meeting 2021

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