Dear Sir.
We are academic users of MacroModel Version 7.0.
Currently we are running MD and FEP procedures with a
protein-ligand complex using ffld AMBER* (the version
implemented in MacroModel). The ligand is a small
molecule which consists of a C-PO3 bond (the molecule is
a bisphosphonate, i.e. it has a O3P-C-PO3 group), and the
P-C-P bonding is able to coordinate different mono and
divalent metal cations such as Na, Ca and Mg. The
coordination to the divalent metals is crucial for the
biologic activity of the ligand since the coordination
complex is recognized as the substrate by the enzyme.
Two main problems appeared when the modeling study is
started. Firstly, an error message informed us that the
ffld has no parameters for the C-P bond. And second, it
lacks parameters for the Mg cation. As the program fails
to process the structure of interest, we ask you for the
following:
i) are there AMBER ffld parameters for the C-P bond? If
so, how could they be obtained? Could be installed in
MacroModel Version 7.0?
ii) are there AMBER ffld parameters for magnesium? How
could we get them? Could they be installed in MacroModel
Version 7.0?
iii) if there are not available ffld parameters for the
divalent cation, how could be parametrized AMBER? Is it
possible to deduce the parameters from the coordinates of
an x-ray crystallographic structure? (note that there are
available three structures in the CSD).
iv) in the worst case, if there were not parameters for
the C-P bond and the cation at all, what could be the
best solution? For example, as the P-C-P bond do not will
be mutated in the procedure, could it be deleted?,
replaced by an analogous group (though the central atom
must be sp3)?, and then run (with sufficient accuracy?)
the process. Could this portion be frozen and the other
part of of the molecule subjected to the dynamics?
Any kind of help will be very welcome.
Thanks in advance,
Daniel Fernandez & Jose M. Delfino.
************************************************************
Jose M. Delfino, Ph.D.
Professor
Department of Biological Chemistry and IQUIFIB
(UBA-CONICET)
School of Pharmacy and Biochemistry
University of Buenos Aires
Junin 956
1113 Buenos Aires
Argentina
Tel. 54 11 4962 5506, 54 11 4964 8289/8290/8291,
extensions 102 (lab) and 116 (office)
Fax. 54 11 4962 5457
Received on Tue Jun 24 2003 - 06:53:01 PDT
