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Molecular mechanics parameters for the FapydG DNA lesion.

ABSTRACT: FapydG is a common oxidative DNA lesion involving opening of the imidazole ring. It shares the same precursor as 8-oxodG and can be excised by the same enzymes as 8-oxodG. However, the loss of the aromatic imidazole in FapydG results in a reduction of the double bond character between C5 and N7, with an accompanying increase in conformational flexibility. Experimental characterization of FapydG is hampered by high reactivity, and thus it is desirable to investigate structural details through computer simulation. We show that the existing Amber force field parameters for FapydG do not reproduce X-ray structural data. We employed quantum mechanics energy profile calculations to derive new molecular mechanics parameters for the rotation of the dihedral angles in the eximidazole moiety. Using these parameters, all-atom simulations in explicit water reproduce the nonplanar conformation of cFapydG in the crystal structure of the complex with L. lactis glycosylase Fpg. We note that the nonplanar structure is stabilized by an acidic residue that is not present in most Fpg sequences. Simulations of the E-->S mutant, as present in E. coli, resulted in a more planar conformation, suggesting that the highly nonplanar form observed in the crystal structure may not have direct biological relevance for FapydG.

SUBMITTER: Song K

PROVIDER: S-EPMC4226240 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Molecular mechanics parameters for the FapydG DNA lesion.

Song Kun K Hornak Viktor V de los Santos Carlos C Grollman Arthur P AP Simmerling Carlos C

Journal of computational chemistry 20080101 1

FapydG is a common oxidative DNA lesion involving opening of the imidazole ring. It shares the same precursor as 8-oxodG and can be excised by the same enzymes as 8-oxodG. However, the loss of the aromatic imidazole in FapydG results in a reduction of the double bond character between C5 and N7, with an accompanying increase in conformational flexibility. Experimental characterization of FapydG is hampered by high reactivity, and thus it is desirable to investigate structural details through com ...[more]

PMID: 17551974

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Project description:Direct molecular dynamics (MD) simulation with ab initio quantum mechanical and molecular mechanical (QM/MM) methods is very powerful for studying the mechanism of chemical reactions in a complex environment but also very time-consuming. The computational cost of QM/MM calculations during MD simulations can be reduced significantly using semiempirical QM/MM methods with lower accuracy. To achieve higher accuracy at the ab initio QM/MM level, a correction on the existing semiempirical QM/MM model is an attractive idea. Recently, we reported a neural network (NN) method as QM/MM-NN to predict the potential energy difference between semiempirical and ab initio QM/MM approaches. The high-level results can be obtained using neural network based on semiempirical QM/MM MD simulations, but the lack of direct MD samplings at the ab initio QM/MM level is still a deficiency that limits the applications of QM/MM-NN. In the present paper, we developed a dynamic scheme of QM/MM-NN for direct MD simulations on the NN-predicted potential energy surface to approximate ab initio QM/MM MD. Since some configurations excluded from the database for NN training were encountered during simulations, which may cause some difficulties on MD samplings, an adaptive procedure inspired by the selection scheme reported by Behler [ Behler Int. J. Quantum Chem. 2015 , 115 , 1032 ; Behler Angew. Chem., Int. Ed. 2017 , 56 , 12828 ] was employed with some adaptions to update NN and carry out MD iteratively. We further applied the adaptive QM/MM-NN MD method to the free energy calculation and transition path optimization on chemical reactions in water. The results at the ab initio QM/MM level can be well reproduced using this method after 2-4 iteration cycles. The saving in computational cost is about 2 orders of magnitude. It demonstrates that the QM/MM-NN with direct MD simulations has great potentials not only for the calculation of thermodynamic properties but also for the characterization of reaction dynamics, which provides a useful tool to study chemical or biochemical systems in solution or enzymes.

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Molecular mechanics parameters for the FapydG DNA lesion.

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Molecular mechanics parameters for the FapydG DNA lesion.

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