[gmx-users] Free Energy Calculations for linkage change

Sai Kumar Ramadugu sramadugu at gmail.com
Wed Apr 7 22:58:57 CEST 2010

Dear All,
   I have an disaccharide bound to a C-type lectin. The sequence of
disaccharide is beta-galactose1-4beta-GlcNAc. The 3'OH and 4'OH  of
beta-galactose coordinate to the Ca2+ at the active site. FRET experiments
have shown that if the disaccharide linkage is changed to
beta-galactose1-3beta-GlcNAc then the binding affinity drops to 20 fold. I
have attached both disaccharides in the figure. The left side residue is
galactose and right side residue is N-Acetylgalactoseamine. .
In order to do a free energy perturbation and find the relative free energy
of binding for these two ligands, I have to slowly change the linkage from
beta1-4 to beta1-3. If you look at the models of both disaccharides from the
figure, to convert the beta 1-4 linked disaccharide to beta 1-3 linked
disaccharide, I have to make the the C1 atom of Galactose attached to O4 of
N-Acetylgalactoseamine as H atom and rest of the galactose residue to dummy
atoms. On the other hand I have to grow the residue from H attached to O3 of
N-acetylgalactoseamine to a galactose. The number of atoms involved is 21
atoms. Further the constraints I have is that the sugar should be bound in
right conformation at the active site. So may be I need distance restraints.
Does my approach make any sense? I have seen some papers by others where
they add a fragment or delete a fragment between two ligands. But in my case
the difference is the linkage between two residues.

Thanks for your time in advance.

Sai Ramadugu
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