TY - JOUR
T1 - Prediction of water and metal binding sites and their affinities by using the FoldX force field
AU - Schymkovitz, Joost
AU - Rousseau, Frederic
AU - Martins, Ivo C.
AU - Ferkinghoff-Borg, Jesper
AU - Stricher, Francois
AU - Serrano, Luis
PY - 2005
Y1 - 2005
N2 - The empirical force field Fold-X was developed previously to allow
rapid free energy calculations in proteins. Here, we present an
enhanced version of the force field allowing prediction of the
position of structural water molecules and metal ions, together
called single atom ligands. Fold-X picks up 76% of water molecules
found to interact with two or more polar atoms of proteins in
high-resolution crystal structures and predicts their position to
within 0.8 Å on average. The prediction of metal ion-binding sites
have success rates between 90% and 97% depending on the metal,
with an overall standard deviation on the position of binding of
0.3– 0.6 Å. The following metals were included in the force field:
Mg2+, Ca2+, Zn2+, Mn2+, and Cu2+. As a result, the current version
of Fold-X can accurately decorate a protein structure with biologically
important ions and water molecules. Additionally, the free
energy of binding of Ca2+ and Zn2+ (i.e., the natural logarithm of
the dissociation constant) and its dependence on ionic strength
correlate reasonably well with the experimental data available in
the literature, allowing one to discriminate between high- and
low-affinity binding sites. Importantly, the accuracy of the energy
prediction presented here is sufficient to efficiently discriminate
between Mg2+, Ca2+, and Zn2+ binding.
AB - The empirical force field Fold-X was developed previously to allow
rapid free energy calculations in proteins. Here, we present an
enhanced version of the force field allowing prediction of the
position of structural water molecules and metal ions, together
called single atom ligands. Fold-X picks up 76% of water molecules
found to interact with two or more polar atoms of proteins in
high-resolution crystal structures and predicts their position to
within 0.8 Å on average. The prediction of metal ion-binding sites
have success rates between 90% and 97% depending on the metal,
with an overall standard deviation on the position of binding of
0.3– 0.6 Å. The following metals were included in the force field:
Mg2+, Ca2+, Zn2+, Mn2+, and Cu2+. As a result, the current version
of Fold-X can accurately decorate a protein structure with biologically
important ions and water molecules. Additionally, the free
energy of binding of Ca2+ and Zn2+ (i.e., the natural logarithm of
the dissociation constant) and its dependence on ionic strength
correlate reasonably well with the experimental data available in
the literature, allowing one to discriminate between high- and
low-affinity binding sites. Importantly, the accuracy of the energy
prediction presented here is sufficient to efficiently discriminate
between Mg2+, Ca2+, and Zn2+ binding.
M3 - Journal article
SN - 0027-8424
VL - 102
SP - 10147
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
ER -