Conformational distortions induced by periodically recurring A…A in d(CAG).d(CAG) provide stereochemical rationale for the trapping of MSH2.MSH3 in polyQ disorders
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 struc...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037021003081 |
| _version_ | 1818979550614257664 |
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| author | Yogeeshwar Ajjugal Thenmalarchelvi Rathinavelan |
| author_facet | Yogeeshwar Ajjugal Thenmalarchelvi Rathinavelan |
| author_sort | Yogeeshwar Ajjugal |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T17:01:19Z |
| format | Article |
| id | doaj.art-73e67105447b43a58f9fe117068deeba |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-12-20T17:01:19Z |
| publishDate | 2021-01-01 |
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| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-73e67105447b43a58f9fe117068deeba2022-12-21T19:32:30ZengElsevierComputational and Structural Biotechnology Journal2001-03702021-01-011944474455Conformational distortions induced by periodically recurring A…A in d(CAG).d(CAG) provide stereochemical rationale for the trapping of MSH2.MSH3 in polyQ disordersYogeeshwar Ajjugal0Thenmalarchelvi Rathinavelan1Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana State 502285, IndiaCorresponding author.; Department of Biotechnology, Indian Institute of Technology Hyderabad, Kandi, Telangana State 502285, IndiaCAG 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.http://www.sciencedirect.com/science/article/pii/S2001037021003081CAG repeat expansionPolyglutamine diseasesMSH2.MSH3Molecular dynamics simulationsA…A mismatch |
| spellingShingle | Yogeeshwar Ajjugal Thenmalarchelvi Rathinavelan Conformational distortions induced by periodically recurring A…A in d(CAG).d(CAG) provide stereochemical rationale for the trapping of MSH2.MSH3 in polyQ disorders Computational and Structural Biotechnology Journal CAG repeat expansion Polyglutamine diseases MSH2.MSH3 Molecular dynamics simulations A…A mismatch |
| title | Conformational distortions induced by periodically recurring A…A in d(CAG).d(CAG) provide stereochemical rationale for the trapping of MSH2.MSH3 in polyQ disorders |
| title_full | Conformational distortions induced by periodically recurring A…A in d(CAG).d(CAG) provide stereochemical rationale for the trapping of MSH2.MSH3 in polyQ disorders |
| title_fullStr | Conformational distortions induced by periodically recurring A…A in d(CAG).d(CAG) provide stereochemical rationale for the trapping of MSH2.MSH3 in polyQ disorders |
| title_full_unstemmed | Conformational distortions induced by periodically recurring A…A in d(CAG).d(CAG) provide stereochemical rationale for the trapping of MSH2.MSH3 in polyQ disorders |
| title_short | Conformational distortions induced by periodically recurring A…A in d(CAG).d(CAG) provide stereochemical rationale for the trapping of MSH2.MSH3 in polyQ disorders |
| title_sort | conformational distortions induced by periodically recurring a a in d cag d cag provide stereochemical rationale for the trapping of msh2 msh3 in polyq disorders |
| topic | CAG repeat expansion Polyglutamine diseases MSH2.MSH3 Molecular dynamics simulations A…A mismatch |
| url | http://www.sciencedirect.com/science/article/pii/S2001037021003081 |
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