Dependence of the mechanical intersubunit communication of a dimeric protein to specific mutation as revealed by molecular dynamics simulation

Falconi, Mattia; Venerini, Francesca; Desideri, Alessandro

doi:10.1016/s0167-7322(99)00108-7

Cited by 3 publications

(3 citation statements)

References 25 publications

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“…The overall protein core, corresponding to the ␤-barrel, has comparable fluctuations in both the native and mutated enzyme. From this picture it can be estimated that in the mutant the coupling between the two subunits may transduce flexibility to the active site loops through a more rigid inter-subunit interface, as already suggested in previous MD simulations of eukaryotic SOD (Falconi et al, 1996;Chillemi et al, 1997;Falconi et al, 1999).…”

Section: Molecular Dynamics Simulationssupporting

confidence: 56%

Dynamics-Function Correlation in Cu, Zn Superoxide Dismutase: A Spectroscopic and Molecular Dynamics Simulation Study

Falconi

Stroppolo

Cioni

et al. 2001

Biophysical Journal

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A single mutation (Val29-->Gly) at the subunit interface of a Cu, Zn superoxide dismutase dimer leads to a twofold increase in the second order catalytic rate, when compared to the native enzyme, without causing any modification of the structure or the electric field distribution. To check the role of dynamic processes in this catalytic enhancement, the flexibility of the dimeric protein at the subunit interface region has been probed by the phosphorescence and fluorescence properties of the unique tryptophan residue. Multiple spectroscopic data indicate that Trp83 experiences a very similar, and relatively hydrophobic, environment in both wild-type and mutant protein, whereas its mobility is distinctly more restrained in the latter. Molecular dynamics simulation confirms this result, and provides, at the molecular level, details of the dynamic change felt by tryptophan. Moreover, the simulation shows that the loops surrounding the active site are more flexible in the mutant than in the native enzyme, making the copper more accessible to the incoming substrate, and being thus responsible for the catalytic rate enhancement. Evidence for increased, dynamic copper accessibility also comes from faster copper removal in the mutant by a metal chelator. These results indicate that differences in dynamic, rather than structural, features of the two enzymes are responsible for the observed functional change.

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Section: Molecular Dynamics Simulationssupporting

confidence: 56%

Dynamics-Function Correlation in Cu, Zn Superoxide Dismutase: A Spectroscopic and Molecular Dynamics Simulation Study

Falconi

Stroppolo

Cioni

et al. 2001

Biophysical Journal

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“…The RMSF asymmetry; the presence of strong anti-correlation motion between monomers; and the h-bond network in the wild type enzyme, therefore, are indicative of a functional cooperative mechanism in the wild type protein that is lost upon C313Y mutation. Actually functional communications between monomers, linked to an asymmetric behavior, have been already observed in Superoxide Dismutase ( Falconi et al, 1996 ; Chillemi et al, 1997 ), together with their perturbations upon mutations ( Falconi et al, 1999 ). A functional break of the tetramer symmetry has been also recently observed in the p53-DNA complex ( D’Abramo et al, 2015 ).…”

Section: Discussionmentioning

confidence: 97%

Structural and Dynamic Characterization of the C313Y Mutation in Myostatin Dimeric Protein, Responsible for the “Double Muscle” Phenotype in Piedmontese Cattle

2016

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The knowledge of the molecular effects of the C313Y mutation, responsible for the “double muscle” phenotype in Piedmontese cattle, can help understanding the actual mechanism of phenotype determination and paves the route for a better modulation of the positive effects of this economic important phenotype in the beef industry, while minimizing the negative side effects, now inevitably intersected. The structure and dynamic behavior of the active dimeric form of Myostatin in cattle was analyzed by means of three state-of-the-art Molecular Dynamics simulations, 200-ns long, of wild-type and C313Y mutants. Our results highlight a role for the conserved Arg333 in establishing a network of short and long range interactions between the two monomers in the wild-type protein that is destroyed upon the C313Y mutation even in a single monomer. Furthermore, the native protein shows an asymmetry in residue fluctuation that is absent in the double monomer mutant. Time window analysis on further 200-ns of simulation demonstrates that this is a characteristic behavior of the protein, likely dependent on long range communications between monomers. The same behavior, in fact, has already been observed in other mutated dimers. Finally, the mutation does not produce alterations in the secondary structure elements that compose the characteristic TGF-β cystine-knot motif.

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“…4(b) indicate that the differences for the e-loops become apparent only after 2 ns. In fact, the calculations we have carried out are much longer than most other previous molecular simulation studies on superoxide dismutase which, in most cases, only up to the order of 1 ns were achieved [22,23]. However, with improved parallelization techniques (as employed in DL_POLY_3 software) and advances in computational capabilities (such as the HPCx), bio-molecular simulations of up to 10s of nanoseconds can now be routinely achieved.…”

Section: Resultsmentioning

confidence: 99%

Structural investigation of human wild-type Cu, Zn superoxide dismutase – a biomolecular case study using DL_POLY_3

Yong¹,

Smith²,

Strange³

et al. 2006

Molecular Simulation

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Dependence of the mechanical intersubunit communication of a dimeric protein to specific mutation as revealed by molecular dynamics simulation

Cited by 3 publications

References 25 publications

Dynamics-Function Correlation in Cu, Zn Superoxide Dismutase: A Spectroscopic and Molecular Dynamics Simulation Study

Dynamics-Function Correlation in Cu, Zn Superoxide Dismutase: A Spectroscopic and Molecular Dynamics Simulation Study

Structural and Dynamic Characterization of the C313Y Mutation in Myostatin Dimeric Protein, Responsible for the “Double Muscle” Phenotype in Piedmontese Cattle

Structural investigation of human wild-type Cu, Zn superoxide dismutase – a biomolecular case study using DL_POLY_3

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