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Issue 6, 2007
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Molecular dynamics simulation of thermal unfolding of Thermatoga maritima DHFR

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Abstract

Molecular dynamics simulations of the temperature-induced unfolding reaction of native dimeric dihydrofolate reductase from the hyperthermophile Thermatoga maritima (TmDHFR) and the experimentally inaccessible TmDHFR monomer were carried out at 400 K, 450 K and 500 K. The results revealed that the unfolding of TmDHFR subunits followed a similar path to that of the monomeric DHFR from the mesophile E. coli (EcDHFR). An initial collapse of the adenosine-binding domain (ABD) was followed by the loss of the N-terminal and loop domains (NDLD). Interestingly, the elements of the secondary structure of the isolated TmDHFR monomer were maintained for significantly longer periods of time for the hyperthermophilic enzyme, suggesting that subunit stability contributes to the enhanced resistance of TmDHFR to temperature-induced unfolding. The interactions between the subunits of the TmDHFR dimer led to a stabilisation of the NDLD. The hydrogen bonds between residues 140–143 in βG of one subunit and residues 125–127 in βF of the other subunit were retained for significant parts of the simulations at all temperatures. These intermolecular hydrogen bonds were lost after the unfolding of the individual subunits. The high stability of the dimer mediated by strong intersubunit contacts together with an intrinsically enhanced stability of the subunits compared to EcDHFR provides a molecular rational for the higher stability of the thermophilic enzyme. The computed unfolding pathways suggest that the partly folded dimer may be a genuine folding intermediate.

Graphical abstract: Molecular dynamics simulation of thermal unfolding of Thermatoga maritima DHFR

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Publication details

The article was received on 03 Aug 2006, accepted on 01 Dec 2006 and first published on 18 Dec 2006


Article type: Paper
DOI: 10.1039/B611210B
Phys. Chem. Chem. Phys., 2007,9, 711-718

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    Molecular dynamics simulation of thermal unfolding of Thermatoga maritima DHFR

    J. Pang and R. K. Allemann, Phys. Chem. Chem. Phys., 2007, 9, 711
    DOI: 10.1039/B611210B

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