Importance of Base-pair Probing for Mismatch Recognition

a 2019

Importance of Base-pair Probing for Mismatch Recognition

BOUCHAL, Tomáš, Ivo DURNÍK and Petr KULHÁNEK

Basic information

Original name

Importance of Base-pair Probing for Mismatch Recognition

Authors

BOUCHAL, Tomáš (203 Czech Republic, belonging to the institution), Ivo DURNÍK (203 Czech Republic, belonging to the institution) and Petr KULHÁNEK (203 Czech Republic, guarantor, belonging to the institution)

Edition

Advances in Noncanonical Nucleic Acids, Rogaška Slatina, Slovenia, 2019

Other information

Language

English

Type of outcome

Konferenční abstrakt

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

Slovenia

Confidentiality degree

není předmětem státního či obchodního tajemství

RIV identification code

RIV/00216224:14740/19:00111009

Organization unit

Central European Institute of Technology

ISBN

978-961-6104-47-0

Keywords in English

Base-pair Probing; Mismatch Recognition

Abstract

V originále

Stability of canonical base pairs is essential for the integrity of double-stranded DNA (dsDNA) and fidelity of genetic information inheritance, yet many other non-canonical pairs (mismatches) can appear due to replication error. Because mismatches within dsDNA are pathological to various extent, several proteins continuously search for such lesions. One of them is MutS from mismatch repair pathway. Despite many suggestions, mechanism of mismatch detection is not well understood. Thus, we evaluated thermodynamic stability of base pairs composed of 26 unique combinations of A, G, T, and C nucleobases in anti-anti, anti-syn and syn-anti conformations in the central part of 13-nt long palindromic dsDNA by biased molecular dynamics simulations. The bias was introduced through two base-pair parameters, Opening, and Shear, which cover all possible arrangements of nucleobases in the base pair plane. In total, we identified and characterized almost one hundred different free-energy minima. We found excellent agreement between calculated free energy minima and experimental structures of mismatches in both free DNA and DNA complexed with the MutS enzyme. The latter suggests that MutS evolved in such a way that the mismatch recognition is achieved by probing a mismatch towards the minor groove, where mismatches exhibit stable albeit energetically less favorable structures already in the free form while the canonical base pairs do not. We also found that opening of mismatch towards minor groove provides better discrimination from the canonical base pairs than previously suggested bending of DNA. This finding can be helpful in better understanding of sequence-dependent mutability or designing chemical substances targeting damaged DNA.

Links

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

BOUCHAL, Tomáš, Ivo DURNÍK and Petr KULHÁNEK. Importance of Base-pair Probing for Mismatch Recognition. In Advances in Noncanonical Nucleic Acids, Rogaška Slatina, Slovenia. 2019. ISBN 978-961-6104-47-0.

@proceedings{1572016,
   author = {Bouchal, Tomáš and Durník, Ivo and Kulhánek, Petr},
   booktitle = {Advances in Noncanonical Nucleic Acids, Rogaška Slatina, Slovenia},
   keywords = {Base-pair Probing; Mismatch Recognition},
   language = {eng},
   isbn = {978-961-6104-47-0},
   title = {Importance of Base-pair Probing for Mismatch Recognition},
   year = {2019}
}

TY  - CONF
ID  - 1572016
AU  - Bouchal, Tomáš - Durník, Ivo - Kulhánek, Petr
PY  - 2019
TI  - Importance of Base-pair Probing for Mismatch Recognition
SN  - 9789616104470
KW  - Base-pair Probing
KW  - Mismatch Recognition
N2  - Stability of canonical base pairs is essential for the integrity of double-stranded DNA (dsDNA) and fidelity of genetic information inheritance, yet many other non-canonical pairs (mismatches) can appear due to replication error. Because mismatches within dsDNA are pathological to various extent, several proteins continuously search for such lesions. One of them is MutS from mismatch repair pathway. Despite many suggestions, mechanism of mismatch detection is not well understood. Thus, we evaluated thermodynamic stability of base pairs composed of 26 unique combinations of A, G, T, and C nucleobases in anti-anti, anti-syn and syn-anti conformations in the central part of 13-nt long palindromic dsDNA by biased molecular dynamics simulations. The bias was introduced through two base-pair parameters, Opening, and Shear, which cover all possible arrangements of nucleobases in the base pair plane. In total, we identified and characterized almost one hundred different free-energy minima. We found excellent agreement between calculated free energy minima and experimental structures of mismatches in both free DNA and DNA complexed with the MutS enzyme. The latter suggests that MutS evolved in such a way that the mismatch recognition is achieved by probing a mismatch towards the minor groove, where mismatches exhibit stable albeit energetically less favorable structures already in the free form while the canonical base pairs do not. We also found that opening of mismatch towards minor groove provides better discrimination from the canonical base pairs than previously suggested bending of DNA. This finding can be helpful in better understanding of sequence-dependent mutability or designing chemical substances targeting damaged DNA.
ER  -

BOUCHAL, Tomáš, Ivo DURNÍK and Petr KULHÁNEK. Importance of Base-pair Probing for Mismatch Recognition. In \textit{Advances in Noncanonical Nucleic Acids, Rogaška Slatina, Slovenia}. 2019. ISBN~978-961-6104-47-0.

Detailed Information on Publication Record