Abstract
CAG repeat instability causes a number of neurodegenerative disorders. The unusual hairpin stem structure formed by the CAG repeats in DNA traps the human mismatch repair MSH2.MSH3 (Mutsβ) complex. To understand the mechanism behind the abnormal binding of Mutsβ with the imperfect hairpin stem structure formed by CAG repeats, molecular dynamics simulations have been carried out for Mutsβ-d(CAG)2(CAG)(CAG)2.d(CTG)2(CAG)(CTG)2 (1 A…A mismatch) and Mutsβ-d(CAG)5.d(CAG)5 (5 mismatches, wherein, A…A occurs periodically) complexes. The interaction of MSH3 residue Tyr245 at the minor groove side of A…A, an essential interaction responsible for the recognition by Mutsβ, are retained in both the cases. Nevertheless, the periodic unwinding caused by the nonisostericity of A…A with the flanking canonical base pairs in d(CAG)5.d(CAG)5 distorts the regular B-form geometry. Such an unwinding exposes one of the A…A mismatches (that interacts with Tyr245) at the major groove side and also facilitates the on and off hydrogen bonding interaction with Lys546 sidechain (MSH2-domain-IV). In contrast, kinking of the DNA towards the major groove in Mutsβ-d(CAG)2(CAG)(CAG)2.d(CTG)2(CAG)(CTG)2 doesn't facilitate such an exposure of the bases at the major groove. Further, the unwinding of the helix in d(CAG)5.d(CAG)5 enhances the tighter binding between MSH2-domain-I and d(CAG)5.d(CAG)5 at the major groove side as well as between MSH3-domain-I and MSH3-domain-IV. Markedly, such enhanced interactions are absent in Mutsβ-d(CAG)2(CAG)(CAG)2.d(CTG)2(CAG)(CTG)2 that has a single A…A mismatch. Thus, the above-mentioned enhancement in intra- and inter- molecular interactions in Mutsβ-d(CAG)5.d(CAG)5 provide the stereochemical rationale for the trapping of Mutsβ in CAG repeat expansion disorders.