Onset of Mismatch Repair by the Human Mismatch Repair Protein, MutSbeta for a Biosensing Device

Abstract

AbstractDeficiency of MutSbeta protein has been proven to be a cause of Lynch Syndrome, which leads to hereditary colorectal cancer. In the absence of MutSbeta, or the energy source to initiate the conformational change of MutSbeta, the DNA repair pathway would not detect the DNA base pairing errors resulting in a failure to proceed. To examine the essential role of MutSbeta and the interface between MutSbeta and a mismatched DNA strand, 500ns of molecular dynamics simulations were performed and the results were compared with the controls. It is found that during the first 100ns, the outermost domain of MutSbeta (chain BP4) gets hold of the DNA, and the inner domains (AP1 and BP1) prepare to scan the DNA strand. An RMSD of 5-7Å for the control MutSbeta compared to 3-6.5Å in the presence of a mismatched DNA indicate that starting ∼75ns, MutSbeta stabilizes and initiates the scanning of the mismatched DNA. The reduction of the distance between the two biomolecules by ∼16Å, increase of Van der Waals energies by ∼75 kCal/mol and a crucial role played by the interfacial water molecules and their hydrogen bonds during the next 100ns also supports the manipulative nature and initiation of scanning by MutSbeta.Author SummaryAbout 1 and 23 men and 1 and 26 women have the chances of developing colorectal cancer and the chances only increase with old age. Cancer typically develops from mutated DNA, which emphasizes the importance of understanding how proteins a part of the DNA repair pathway process interact with a mutated strand of DNA. One such protein, MutSbeta, is the first protein that initiates the repair pathway process and scans DNA for any mutations. As the initiator, a deficiency of MutSbeta leads to higher chances of mutated DNA going undetected, and therefore forming cancerous cells. Using 3D simulations, we analyzed the interactions between MutSbeta and a mutated DNA strand. We found that the two outer domains, AP4 and BP4 grab hold of the DNA strand while the inner clamps, AP1 and BP1 scan the DNA strand. It was also discovered that Van der Waals play a more dominant role compared to electrostatics in terms of the driving force behind the interactions between DNA and MutSbeta. Overall, our data supported the attractive nature of MutSbeta towards DNA and its stability as it initiates the scanning process. Furthermore, this data was used to verify the presence of MutSbeta for a biosensor that was built previously; owing to the significance and applicatory effects of this work.