ISIS Report 25/10/05
Water Smoothing Protein Relationships
How proteins get into shape through water chains. Dr.
Mae-Wan Ho
A fully referenced version
of this article is posted on ISIS members’ website. Details here
Proteins consist of linear chains of amino acids joined up together when first
synthesized in the cell, but soon adopt various secondary and tertiary structures.
Most of them end up in a folded shape that is important for the function they
serve; at least this is the conventional view (see "Strong medicine for cell
biology", SiS
24).
For a long time,
researchers have acknowledged the importance of water in protein folding,
but only in a negative role, in that it is the avoidance
of water in hydrophobic (water-hating) interactions that determines how the
chain folds up. As yet, most computer algorithms for predicting the folded
structure of proteins do not take water into account.
When the protein
chain folds up, amino acids from widely separated parts of the chain come
into contact, but it is difficult to predict which ones will end up in contact.
The team led by Peter Wolynes in UC San Diego and University of Illinois at
Urbana in the United States first investigated what would happen if these
specific interactions between amino acids were mediated by water. They developed
a model based on information available in the bioinformatic database to derive
potentials both for direct contact between pairs of amino acids on the protein
chain and indirect contact through one or more molecules of water.
When both potentials
were used in computer simulations, a smooth recognition of the diverse binding
partners takes place, in contrast to runs in which only direct contact potentials
were used.
The researchers
then went further, and showed that water plays an important role not only
in helping amino acids find their contact partners, but also in how the whole
chain folds up.
For their computer
simulation, they used the ‘AM Hamiltonian’ molecular dynamics model as a starting
point. A ‘Hamiltonian’ is an energy function - named after the mathematician
who invented it - which is characteristic of a given process. The AM Hamiltonian
has two main components: one based on the physics of the backbone of the protein
chain, the “backbone” component, and the other based on knowledge of the specific
amino-acid sequence in the chain and their energy potentials, collectively
referred to as the “AM/C (contact)” component of the Hamiltonian. The ‘AM’
part describes interactions between all pairs of amino acids separated in
sequence between 3 and 12 neighbours, which have been obtained for a set of
156 proteins in the bioinformatic database. The ‘C’ part applies to contacts
between amino acids separated by >12 neighbours in the sequence, and consists
of several potentials applying to different range of contact distances between
the amino acids.
Wolynes’ group
incorporated into their model the first direct contact C potential, and added
a ‘water potential’ W for contact distances between 6.5 and 9.5Å (an angstrom,
or 10-10m).
This gave a significant improvement in protein structure
prediction. “Wetting” the Hamiltonian with water improved the predicted structure,
especially for large proteins.
It seems that highly charged amino acids don’t like to
be in direct contact, and such contacts are unstable, whereas the contact
is stabilized if mediated by water. That is because a lot of energy has to
be spent getting these hydrophilic (water-loving) groups to let go of water
molecules that they are already bound to, so they tend to contact other highly
charged groups via one or two water intermediates. Even more interesting is
that not only oppositely charged residues attract each other through water,
but so do groups with the same charge, which suggests that the one or the
other of the groups in contact must be changing its sign, or else the contact
partners fluctuate coherently together, ie, take turns being the charged or
uncharged (rather like dancing rapidly back and forth perfectly in step).
Simulations were
done on 14 proteins, from small to large. For all but three proteins, including
the water potential significantly improved the fit to the native folded protein;
some of the improvements were very striking, and improvements were especially
consistent for proteins larger than 115 residues.
The results
show that water not only induced protein folding and binding, but also actively
participates via long-range water-mediated contacts. Adding water may improve
protein docking, protein and drug design strategies, and contribute to understanding
the important role played by water in the function of proteins.
There are other
simulations of protein folding in water that provide good quantitative agreement
with experimental data. For example, the research team at Stanford University
has a model that takes explicit atomistic account of all water-water, water-protein
interactions in order to arrive at the folded state [3]. A word of warning
is in order in case you think that this computer simulation accurately represents
how proteins fold. It takes about 300 years for a computer to simulate a small
peptide of 23 amino acid residues to fold into shape in 3938 water molecules.
By running simulations simultaneously on some 140 000 individual computers
around the world, the researchers took just over three weeks [4]. The protein
itself, however, folds to perfection in several microseconds.
| 
