FEP & different ligands

From: satya work (satya.work_at_gmail.com)
Date: Mon Dec 11 2006 - 01:20:06 CST

Hello all,

I am interested in using FEP, as implemented in NAMD, to compute free energy
difference (1) between two ligands (ethanol->butanol) that bind to a protein
(2) mutating a particular residue in a protein. I intend to perform (1) by
mutating ethanol->butanol in water & in the presence of protein to complete
the thermodynamic cycle. for (2), I am trying to understand the example
presented in the tutorial (may be more questions will follow)

But I am slightly confused about some fundamental aspects of implementation
of FEP:

1. what are the interactions present in the system in the case of
2. are the intra-bond interactions of individual ligands still present? i
mean are the ligands still 'bonded together' at end points?
3. are only the non-bonded interactions (LJ & Coulomb) scaled with 'lambda'?

4. can FEP as implemented in NAMD be used in a case where there are no
'common chemical groups' between two ligands?
5. for a case of mutating residue X -> Y in a protein embedded in lipid
environment, what thermodynamic cycle is best suited (is it even advisable
to address this problem in case of a membrane protein, with all additional
complexity and probably long time scales?)
6. if the mutation is from a neutral to charged amino acid, what is the best
way to create the hybrid topology with respect to charges? ( iam assuming i
cannot use the charges 'as is' from CHARMM parameter set)


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