{"title":"Molecular Dynamical Investigation of the 7,8-dihydro-8-oxoguanine Mutation in dsDNA","authors":"I. Dementyev, Ashkan Karimi","doi":"10.26443/msurj.v16i1.56","DOIUrl":null,"url":null,"abstract":"Background: The oxidization of a Guanine (G) base pair to 7,8-dihydro-8-oxoguanine (OG) is one of the most common DNA mutations. OG mutations can undergo a regular Watson-Crick base-pairing, or a reverse Hoogsteen (HG) base-pairing, especially in OG:A mismatches. While the causes of these mutations are well-understood, the kinetic and energetic characteristics of this new pseudo-base have never been fully investigated, especially at temperatures around biological function (17-37°C).\nMethods: We created a simulation to derive the Free Energy Surface (FES) of OG:C and OG:A Hoogsteen to Watson-Crick base-pair (bp) transitions under multiple temperatures, relative to 2 collective geometric variables: the dihedral Chi and the pseudo-dihedral CPD angle. To make the simulation, we used the relatively recent Metadynamics algorithms in conjunction with GROMACS 2020.2.\nResults: The lowest free energy increased linearly with increasing temperatures (17-37°C). Major Chi and CPD rotations at these minima varied heavily for 27°C and 32°C (the largest was seen in the former), but stayed relatively similar for other temperatures, indicating a highly sensitive relationship to temperature, likely due to DNA flexibility, quantum mechanical (QM) effects, and hydrogen bonding. Free energies had a weak negative linear relationship, and free energy hypersurfaces were given for studied temperatures of 17-37°C. Human body temperature (37°C) results were also included and explained. The simulations showed why OG:A Hoogsteen bps often occur in organisms and are energetically preferable to standard Watson-Crick. OG:C HG base pairings are determined to likely be not as common as OG:A HG.\nLimitations: Future investigations must focus on discovering rate constants of these base-pairs, as time constraints did not permit them to be done here, as well as more QM-focused simulations.","PeriodicalId":91927,"journal":{"name":"McGill Science undergraduate research journal : MSURJ","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2021-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"McGill Science undergraduate research journal : MSURJ","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.26443/msurj.v16i1.56","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 1
Abstract
Background: The oxidization of a Guanine (G) base pair to 7,8-dihydro-8-oxoguanine (OG) is one of the most common DNA mutations. OG mutations can undergo a regular Watson-Crick base-pairing, or a reverse Hoogsteen (HG) base-pairing, especially in OG:A mismatches. While the causes of these mutations are well-understood, the kinetic and energetic characteristics of this new pseudo-base have never been fully investigated, especially at temperatures around biological function (17-37°C).
Methods: We created a simulation to derive the Free Energy Surface (FES) of OG:C and OG:A Hoogsteen to Watson-Crick base-pair (bp) transitions under multiple temperatures, relative to 2 collective geometric variables: the dihedral Chi and the pseudo-dihedral CPD angle. To make the simulation, we used the relatively recent Metadynamics algorithms in conjunction with GROMACS 2020.2.
Results: The lowest free energy increased linearly with increasing temperatures (17-37°C). Major Chi and CPD rotations at these minima varied heavily for 27°C and 32°C (the largest was seen in the former), but stayed relatively similar for other temperatures, indicating a highly sensitive relationship to temperature, likely due to DNA flexibility, quantum mechanical (QM) effects, and hydrogen bonding. Free energies had a weak negative linear relationship, and free energy hypersurfaces were given for studied temperatures of 17-37°C. Human body temperature (37°C) results were also included and explained. The simulations showed why OG:A Hoogsteen bps often occur in organisms and are energetically preferable to standard Watson-Crick. OG:C HG base pairings are determined to likely be not as common as OG:A HG.
Limitations: Future investigations must focus on discovering rate constants of these base-pairs, as time constraints did not permit them to be done here, as well as more QM-focused simulations.