Assessing the Importance of Proton Transfer Reactions in DNA
详细信息 查看全文
- 作者：Denis Jacquemin ; Jos茅 Z煤帽iga ; Alberto Requena ; Jos茅 Pedro C茅ron-Carrasco
- 刊名：Accounts of Chemical Research
- 出版年：2014
- 出版时间：August 19, 2014
- 年：2014
- 卷：47
- 期：8
- 页码：2467-2474
- 全文大小：423K
- ISSN：1520-4898
文摘
Conspectus
Although engineered by millions of years of evolution, the cellular machinery is not flawless, and errors regularly appear during DNA replication. The subsequent alteration of the stored genetic message results in a mutation and might be the starting point of important health disorders. The question therefore is what causes DNA mutations?
All living organisms are constantly exposed to a number of external agents such as free radicals and to radiation, which may lead to induced mutations. There are also mutations happening without invoking the action of any exogenous element, the so-called spontaneous mutations. The former can be partially controlled by avoiding exposure to high-risk environments, while the latter are more intriguing because their origin is unclear and difficult to determine. As noted by Watson and Crick when they first discovered the DNA structure, the correct replication of DNA rests on the assumption that the base pairs remain in their most stable, canonical form. However, protons along the interbase hydrogen-bond network are not static entities. They can in fact interchange their positions in DNA bases through proton transfer (PT) reactions before strands unwind, giving rise to noncanonical structures defined as rare tautomers. The importance of these rare tautomers was also cleverly anticipated by Watson and Crick and some years later claimed by L枚wdin to be a source of spontaneous mutations. In Watson and Crick鈥檚 words: 鈥淚t would be of interest to know the precise difference in free energy between the various tautomeric forms under physiological conditions.鈥?Unfortunately, rare tautomeric forms are very difficult to detect, so no direct and accurate free energy measure has been discerned. In contrast, theoretical chemistry is making good progress toward the quantification of PT reactions in DNA and their biological consequences.
This Account touches upon the theoretical studies devoted to appraising the importance of rare tautomers as promoters of spontaneous mutations. We focus in particular on the crucial role played by the biological environment on DNA stability. It has now been demonstrated that valuable macroscopic predictions require not only highly accurate theories but also refined chemical models. Hybrid quantum mechanics/molecular mechanics (QM/MM) simulations performed on short but complete DNA sequence fragments emerge in this context as the most adequate tools. In addition, these methods can be used to quantify the effect of different external agents on the PT tautomeric equilibria and, eventually, to conveniently handle them. This is the case for the possible alteration of the naturally observed mutation rate by exposure to intense electric fields. Theoretical predictions envision in this respect promising applications of ultrashort electric pulses in medicine to selectively modify the mutated/canonical ratio in DNA.
Although engineered by millions of years of evolution, the cellular machinery is not flawless, and errors regularly appear during DNA replication. The subsequent alteration of the stored genetic message results in a mutation and might be the starting point of important health disorders. The question therefore is what causes DNA mutations?
All living organisms are constantly exposed to a number of external agents such as free radicals and to radiation, which may lead to induced mutations. There are also mutations happening without invoking the action of any exogenous element, the so-called spontaneous mutations. The former can be partially controlled by avoiding exposure to high-risk environments, while the latter are more intriguing because their origin is unclear and difficult to determine. As noted by Watson and Crick when they first discovered the DNA structure, the correct replication of DNA rests on the assumption that the base pairs remain in their most stable, canonical form. However, protons along the interbase hydrogen-bond network are not static entities. They can in fact interchange their positions in DNA bases through proton transfer (PT) reactions before strands unwind, giving rise to noncanonical structures defined as rare tautomers. The importance of these rare tautomers was also cleverly anticipated by Watson and Crick and some years later claimed by L枚wdin to be a source of spontaneous mutations. In Watson and Crick鈥檚 words: 鈥淚t would be of interest to know the precise difference in free energy between the various tautomeric forms under physiological conditions.鈥?Unfortunately, rare tautomeric forms are very difficult to detect, so no direct and accurate free energy measure has been discerned. In contrast, theoretical chemistry is making good progress toward the quantification of PT reactions in DNA and their biological consequences.
This Account touches upon the theoretical studies devoted to appraising the importance of rare tautomers as promoters of spontaneous mutations. We focus in particular on the crucial role played by the biological environment on DNA stability. It has now been demonstrated that valuable macroscopic predictions require not only highly accurate theories but also refined chemical models. Hybrid quantum mechanics/molecular mechanics (QM/MM) simulations performed on short but complete DNA sequence fragments emerge in this context as the most adequate tools. In addition, these methods can be used to quantify the effect of different external agents on the PT tautomeric equilibria and, eventually, to conveniently handle them. This is the case for the possible alteration of the naturally observed mutation rate by exposure to intense electric fields. Theoretical predictions envision in this respect promising applications of ultrashort electric pulses in medicine to selectively modify the mutated/canonical ratio in DNA.