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2015 ; 10
(9
): e0137075
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F429 Regulation of Tunnels in Cytochrome P450 2B4: A Top Down Study of Multiple
Molecular Dynamics Simulations
#MMPMID26415031
Mancini G
; Zazza C
PLoS One
2015[]; 10
(9
): e0137075
PMID26415031
show ga
The root causes of the outcomes of the single-site mutation in enzymes remain by
and large not well understood. This is the case of the F429H mutant of the
cytochrome P450 (CYP) 2B4 enzyme where the substitution, on the proximal surface
of the active site, of a conserved phenylalanine 429 residue with histidine seems
to hamper the formation of the active species, Compound I (porphyrin cation
radical-Fe(IV) = O, Cpd I) from the ferric hydroperoxo (Fe(III)OOH-, Cpd 0)
precursor. Here we report a study based on extensive molecular dynamic (MD)
simulations of 4 CYP-2B4 point mutations compared to the WT enzyme, having the
goal of better clarifying the importance of the proximal Phe429 residue on CYP
2B4 catalytic properties. To consolidate the huge amount of data coming from five
simulations and extract the most distinct structural features of the five species
studied we made an extensive use of cluster analysis. The results show that all
studied single polymorphisms of F429, with different side chain properties: i)
drastically alter the reservoir of conformations accessible by the protein,
perturbing global dynamics ii) expose the thiolate group of residue Cys436 to the
solvent, altering the electronic properties of Cpd0 and iii) affect the various
ingress and egress channels connecting the distal sites with the bulk
environment, altering the reversibility of these channels. In particular, it was
observed that the wild type enzyme exhibits unique structural features as
compared to all mutant species in terms of weak interactions (hydrogen bonds)
that generate a completely different dynamical behavior of the complete system.
Albeit not conclusive, the current computational investigation sheds some light
on the subtle and critical effects that proximal single-site mutations can exert
on the functional mechanisms of human microsomal CYPs which should go rather far
beyond local structure characterization.
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