Folding of the Apolipoprotein A1 Driven by the Salt Concentration as a Possible Mechanism to Improve Cholesterol Trapping - Selected Topics of Computational and Experimental Fluid Mechanics - page 278

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Cl), at different
concentrations for the case of an open conformation of APOA1. One feature that
stands out is the relatively large number of ions in close proximity to the P residue
at 1.8M (blue line). Although P is a non-polar residue, it is highly movable, which
implies that the ions can easily surround it and cause it to have a solvation radius larger
than its own radius, which in turn would compel the neighboring residues to stay at
relatively larger distances from P. This fact, in turn, leads to an open configuration.
In Fig. 6 b there is a uniform distribution of relative distances between the P—residue
and the salt ions at all concentrations; for example, at all salt concentrations in Fig. 6 b
there is approximately the same probability to have ions and the P—residue a distance
r

In Fig. 6 a we show the rdf of the P—residue and the ions (Na

0.7nm apart. The fact that all rdf's in this case follow the same trend at small
relative distances means that these rdf's correspond to configurations where there is
no more room available for the ions to get closer to P. This must be the case when
APOA1 is in a closed conformation, as in Fig. 6 b.

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4 Conclusions

We have shown in this work howatomistically detailedmolecular dynamics computer
simulations can help us understand the folding process in proteins under controlled
physicochemical conditions as, for example, the ionic strength. For this case study
we have chosen APOA1 because of its key role in producing the efflux of fatty acids
in the human blood stream. It was found that, under increasing salt concentration, the
protein undergoes alternatively folding and unfolding. The simulations suggest that
it is driven by the formation of solvation spheres around the most mobile aminoacids
in the APOA1 sequence, competing with the electrostatic interactions. The struc-
tural properties of the protein were characterized through powerful tools such as
the radius of gyration, the end-to-end distance, the mean-square distance matrix, the
Ramachandran plot, and the radial distribution function. In particular, we found that
the P, Y and S residues are moving the most when going from an open to a close
conformation. This work helps elucidate the effect of the charge in APOA1, where
the important sequence turns out to be HLAPYS. The role of the closed configura-
tions should not be underestimated either, for those are precisely the ones thought to
be responsible for the trapping of fatty acids such as cholesterol. Work is presently
under way to determine the association of APOA1 with cholesterol under varying
ionic strength, but it is mandatory to gain first a basic understanding of this protein's
folding at increasing salt content before attempting the study its complexation with
other molecules.

Acknowledgments This project was financed by CONACYT, grant 132056. We would like to
acknowledge many educational conversations on this topic with A. López-Vallejo López. The
authors thank also J. Limón (IFUASLP) for technical support with GPU installation. MABA and
AGG thank the UASLP for its hospitality.