PAVEL JUNG WIRTH
HOFMEISTER STILL
MYSTIFIES
After decades of study, researchers struggle to explain
the ordering of AQUEOUS ION EFFECTS on proteins
ELIZABETH K. WILSON, C&EN WEST COAST NEWS BUREAU
FOR JIFENG ZHANG, research adviser for
bioproduct pharmaceutical development
at Eli Lilly & Co., the solvation of ions in
water has decidedly practical implications.
The topic may appear arcane and academic, yet the behavior of aqueous ions has
profound effects on biological molecules
such as proteins and DNA and, thus, implications for health and disease.
For example, Zhang says, patients
with inflammatory disease may receive a
solution of monoclonal antibodies. The
treatment, dispensed in mass-produced,
prefilled syringes, needs to have a two-year
shelf life. The ions added in the form of salts
or buffer reagents to the protein solution
are crucial for maintaining protein stability.
Different ions are better or worse at preventing aggregation and self-association.
Researchers have no good way to predict
this behavior.
At the core of the problem lies a phenomenon discovered in the late 1800s by
the Czech chemist Franz Hofmeister. He
discovered that certain aqueous ions follow a peculiar order in their increasing or
decreasing ability to precipitate egg whites
in solution. Anions in particular, such as
SO42–, Cl–, and SCN–, follow a seemingly
arbitrary sequence: In this order, they
increasingly can denature and dissolve
proteins, and have increasing or decreasing
effects on many other solution properties,
such as surface tension.
This so-called Hofmeister effect lay
relatively unexplored for de-
cades, until the past 15 years,
when experimental and com-
putational methods allowed
chemists to reexamine the pos-
sible sources of the effect. Since
then, the Hofmeister effect has
formed the subject of hundreds
of papers, with scientists devis-
ing increasingly intricate and di-
verse experiments, with sophis-
ticated theoretical explanations.
Numerous meetings now focus
on the topic, including conferences this
summer hosted by the Telluride Science
Research Center and the Royal Society of
Chemistry.
THE EXPLANATION set forth for decades
was that ions produced long-range effects on the structure of water, leading to
changes in water’s ability to let proteins fall
out of, or stay dissolved in, a solution. That
idea has largely been discarded.
The current view, explains M. Thomas
Record Jr., chemistry and biochemistry
professor at the University of Wisconsin,
Madison, is that Hofmeister effects stem
largely from the varying abilities of different salt ions to replace water at nonpolar
molecular or macroscopic surfaces. But
no theoretical framework can yet predict
these actions.
ION ATTRACTION In this simulation,
SO42– (gray), Cl– (orange), SCN– (yellow),
and Na+ (green) ions cluster around the
backbone of a polypeptide.
Much recent Hofmeister work has fo-
cused on the behavior of ions at interfaces:
between air and water, oil and water, or
protein and water. Some scientists reason
that experiments exploring ion
behavior at air-water interfaces
could eventually shed light on all
interfaces, leading to a general
mechanism.
For example, University of
California, Berkeley, chemistry
professor Richard J. Saykally
performed what he calls “
excruciatingly hard” spectroscopic
experiments on the behavior of
thiocyanate ions in water. Combined with theoretical studies
ORDER IN THE SOLUTION Ions in the Hofmeister
series, from left to right, decrease in ability to augment
surface tension and increase in ability to dissolve proteins.
