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Prediction of reduction potential changes in rubredoxin: a molecular mechanics approach.

ABSTRACT: Predicting the effects of mutation on the reduction potential of proteins is crucial in understanding how reduction potentials are modulated by the protein environment. Previously, we proposed that an alanine vs. a valine at residue 44 leads to a 50-mV difference in reduction potential found in homologous rubredoxins because of a shift in the polar backbone relative to the iron site due to the different side-chain sizes. Here, the aim is to determine the effects of mutations to glycine, isoleucine, and leucine at residue 44 on the structure and reduction potential of rubredoxin, and if the effects are proportional to side-chain size. Crystal structure analysis, molecular mechanics simulations, and experimental reduction potentials of wild-type and mutant Clostridium pasteurianum rubredoxin, along with sequence analysis of homologous rubredoxins, indicate that the backbone position relative to the redox site as well as solvent penetration near the redox site are both structural determinants of the reduction potential, although not proportionally to side-chain size. Thus, protein interactions are too complex to be predicted by simple relationships, indicating the utility of molecular mechanics methods in understanding them.

SUBMITTER: Ergenekan CE

PROVIDER: S-EPMC1303563 | biostudies-literature | 2003 Nov

REPOSITORIES: biostudies-literature

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Prediction of reduction potential changes in rubredoxin: a molecular mechanics approach.

Ergenekan Can E CE Thomas Dustin D Fischer Justin T JT Tan Ming-Liang ML Eidsness Marly K MK Kang ChulHee C Ichiye Toshiko T

Biophysical journal 20031101 5

Predicting the effects of mutation on the reduction potential of proteins is crucial in understanding how reduction potentials are modulated by the protein environment. Previously, we proposed that an alanine vs. a valine at residue 44 leads to a 50-mV difference in reduction potential found in homologous rubredoxins because of a shift in the polar backbone relative to the iron site due to the different side-chain sizes. Here, the aim is to determine the effects of mutations to glycine, isoleuci ...[more]

PMID: 14581187

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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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Prediction of reduction potential changes in rubredoxin: a molecular mechanics approach.

Publications

Prediction of reduction potential changes in rubredoxin: a molecular mechanics approach.

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