Molecular dynamics simulations of the wild type bovine ADP/ATP mitochondrial carrier, and of the single Ala113Pro and double Ala113Pro/Val180Met mutants, embedded in a lipid bilayer, have been carried out for 30 ns to shed light on the structural-dynamical changes induced by the Val180Met mutation restoring the carrier function in the Ala113Pro pathologic mutant. Principal component analysis indicates that, for the three systems, the protein dynamics is mainly characterized by the motion of the matrix loops and of the odd-numbered helices having a conserved proline in their central region. Analysis of the motions shows a different behaviour of single pathological mutant with respect of the other two systems. The single mutation induces a regularization and rigidity of the H3 helix, lost upon the introduction of the second mutation. This is directly correlated to the salt bridge distribution involving residues Arg79, Asp134 and Arg234, hypothesized to interact with the substrate. In fact, in the wild type simulation two stable inter-helices salt bridges, crucial for substrate binding, are present almost over all the simulation time. In line with the impaired ADP transport, one salt interaction is lost in the single mutant trajectory but reappears in the double mutant simulation, where a salt bridge network matching the wild type is restored. Other important structural-dynamical properties, such as the trans-membrane helices mobility, analyzed via the principal component analysis, are similar for the wild type and double mutant while are different for the single mutant, providing a mechanistic explanation for their different functional properties.

Di Marino, D., Oteri, F., MOROZZO DELLA ROCCA, B., Chillemi, G., Falconi, M. (2010). ADP/ATP mitochondrial carrier MD simulations to shed light on the structural–dynamical events that, after an additional mutation, restore the function in a pathological single mutant. JOURNAL OF STRUCTURAL BIOLOGY, 172(3), 225-232 [10.1016/j.jsb.2010.07.015].

ADP/ATP mitochondrial carrier MD simulations to shed light on the structural–dynamical events that, after an additional mutation, restore the function in a pathological single mutant

MOROZZO DELLA ROCCA, BLASCO;FALCONI, MATTIA
2010-01-01

Abstract

Molecular dynamics simulations of the wild type bovine ADP/ATP mitochondrial carrier, and of the single Ala113Pro and double Ala113Pro/Val180Met mutants, embedded in a lipid bilayer, have been carried out for 30 ns to shed light on the structural-dynamical changes induced by the Val180Met mutation restoring the carrier function in the Ala113Pro pathologic mutant. Principal component analysis indicates that, for the three systems, the protein dynamics is mainly characterized by the motion of the matrix loops and of the odd-numbered helices having a conserved proline in their central region. Analysis of the motions shows a different behaviour of single pathological mutant with respect of the other two systems. The single mutation induces a regularization and rigidity of the H3 helix, lost upon the introduction of the second mutation. This is directly correlated to the salt bridge distribution involving residues Arg79, Asp134 and Arg234, hypothesized to interact with the substrate. In fact, in the wild type simulation two stable inter-helices salt bridges, crucial for substrate binding, are present almost over all the simulation time. In line with the impaired ADP transport, one salt interaction is lost in the single mutant trajectory but reappears in the double mutant simulation, where a salt bridge network matching the wild type is restored. Other important structural-dynamical properties, such as the trans-membrane helices mobility, analyzed via the principal component analysis, are similar for the wild type and double mutant while are different for the single mutant, providing a mechanistic explanation for their different functional properties.
2010
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/11 - BIOLOGIA MOLECOLARE
English
Con Impact Factor ISI
Nucleotide carrier; membrane proteins; molecular dynamics; salt bridges; essential dynamics;
http://www.sciencedirect.com/science?_ob=PublicationURL&_cdi=6925&_pubType=J&_acct=C000057972&_version=1&_urlVersion=0&_userid=2606776&md5=d80ee36dd6cb00ade7fa2dbd0538515e&jchunk=172#172
Di Marino, D., Oteri, F., MOROZZO DELLA ROCCA, B., Chillemi, G., Falconi, M. (2010). ADP/ATP mitochondrial carrier MD simulations to shed light on the structural–dynamical events that, after an additional mutation, restore the function in a pathological single mutant. JOURNAL OF STRUCTURAL BIOLOGY, 172(3), 225-232 [10.1016/j.jsb.2010.07.015].
Di Marino, D; Oteri, F; MOROZZO DELLA ROCCA, B; Chillemi, G; Falconi, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/10613
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