Understanding the cation specificeffects on the
aqueous solubility of amino acids: from mono to
polyvalent cations†
L. I. N. Tom
´
e,
a
C. S. R. Sousa,
b
J. R. B. Gomes,
a
O. Ferreira,
*
b
J. A. P. Coutinho
a
and S. P. Pinho
b
The interactions established by mono and polyvalent cations in natural media have important implications
on the structure formation, function and physico-chemical behavior of biomolecules, playing therefore a
critical role in biochemical processes. In order to further elucidate the molecular phenomena behind the
cation specificeffects in biological environments, and clarify the influence of the charge of the ions,
solubility measurements and molecular dynamics simulations were performed for aqueous solutions of
three amino acids (alanine, valine and isoleucine), in the presence of a series of inorganic salts
comprising mono-, di- and trivalent cations (LiCl, Li
2
SO
4
,K
2
SO
4
, CaCl
2
, AlCl
3
and Al
2
(SO
4
)
3
). The
evidence gathered indicates that the mechanism by which (salting-in inducing) polyvalent cations affect
the solubility of amino acids in aqueous solutions is different from that of monovalent cations. A
consistent and refined molecular description of the effect of the cation on the solubility of amino acids
based on specific interactions of the cations with the negatively charged moieties of the biomolecules is
here proposed.
1. Introduction
Electrolyte solutions are the natural environment of life's
essential biomolecules and are recognized as being crucial to
the regulation of their structure formation, function and
physico-chemical behavior, playing thus a central role in several
relevant biochemical processes.
1
The understanding of the
molecular-level mechanisms that govern the solubility, stability
and activity of biocompounds in the presence of salts is there-
fore of utmost importance from a biological, pharmaceutical
and medical point of view, since these might have serious
implications in many diseases and on the development of effi-
cient drugs to ght them.
2–4
In spite of the large amount of work dedicated to this subject
throughout the years,
5–14
the molecular-level description of the
empirical and generally observed Hofmeister effects of ions
5,6,15
is still not consensual, sometimes contradictory, and far from
being denitely established. Mostly, the speciceffects of
cations have been more difficult to explain than those of the
anions
13,14
and have been the focus of a long-standing issue of
research, spearheaded by their presumed involvement in many
human pathological conditions. In particular, a relationship
between the charge and properties of the cations and the nature
of their interactions with biological ligands has not yet been
unambiguously established, constituting a major drawback to
the development of pharmaceutical and medical solutions for
diseases induced by biochemical disorders.
Electron-decient cations play critical roles in the chemistry
of living organisms, mainly because they are attracted by
electron-rich functional groups present in biomolecules,
promoting the formation of natural ligands that perform
important biological functions.
16–18
The interactions of some
ions such as Li, Na, K, Mg, Ca, Zn, Cu, Fe, Co and Mn with
biocompounds, have been extensively studied to understand
the factors behind their binding and selectivity, and their
implications in biochemical processes.
17,18
The biological
interest of trivalent metal ions has motivated as well several
studies, and it has been shown that they can form highly stable
complexes with ligands containing hard electron pair donor
groups.
19–23
These interactions are essential in some cases, but
in others they can interfere or even block vital biochemical
processes.
24
In this respect, the aluminum ion has been
attracting increasing attention, aer numerous negative aspects
of its biological activities, toxicity and possible link to certain
a
CICECO, Departamento de Qu´ ımica, Universidade de Aveiro, Campus Universit´ ario
de Santiago, 3810-193 Aveiro, Portugal
b
LSRE-Laboratory of Separation and Reaction Engineering-Associate Laboratory LSRE/
LCM, Instituto Polit´ ecnico de Bragança, Campus de Santa Apol´ onia, 5301-857,
Bragança, Portugal. E-mail: oferreira@ipb.pt; Fax: +351-273-313051; Tel: +351-273-
303087
† Electronic supplementary information (ESI) available: The pH values measured
for the aqueous saline solutions of the amino acids studied are reported in Table
S1 whereas the positions and intensities of the RDF peak maxima are reported in
Table S2. Snapshots from simulations of aqueous solutions of Ile are shown in
Fig. S1 and S2. RDFs for the interactions between the cations and selected
groups of Ala and Val appear in Fig. S3 and S4. See DOI: 10.1039/c5ra00501a
Cite this: RSC Adv. , 2015, 5, 15024
Received 9th January 2015
Accepted 23rd January 2015
DOI: 10.1039/c5ra00501a
www.rsc.org/advances
15024 | RSC Adv. , 2015, 5, 15024–15034 This journal is © The Royal Society of Chemistry 2015
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