[gmx-users] Re: Size of perturbed groups in FEP

Chris Oostenbrink c.oostenbrink at few.vu.nl
Fri Jan 13 20:48:40 CET 2006

Hello Bruce,

I think that indeed it should be possible to make such large changes, 
but for the problem you describe you may not need to do it. If you use a 
united atom force field, where you C-alpha is one atom together with the 
alpha hydrogen, you can also just invert the stereocenter through the 
covalent interactions. We have explored several possible pathways to 
change the chirality of amino acids in dipeptides in

Y. Zhou, C. Oostenbrink, W.F. van Gunsteren, W.R. Hagen, S.R. de Leeuw, 
J. Jongejan, Mol. Phys., *104* (2005) 1961 - 1969

The problem is, though, that the free energy difference is very very 
small (typically < 1 kJ/mol). We also did a pentapeptide (manuscript 
accepted in JCC) and get similar values.


>Hi everyone,
>I have been wondering about the possibility of doing free energy 
>calculations on D- and L- forms of amino acids incorporated into small 
>peptides but I have no experience in this area and I was just wondering 
>if it is possible to do free energy perturbations on groups as large as 
>the side chains in e.g. isoleucine. It seems to me that changing a 
>hydrogen atom for, say, a methyl group might be OK but what about 
>something as large as -CH(CH3)CH2CH3 ?
>I guess in practice the unit to be perturbed would have to include the 
>backbone carbon plus the hydrogen and side chain in order to go from the 
>D- to the L-form of an amino acid.
>Sorry if this is really basic and obvious but any advice would be 
>greatly appreciated.

Chris Oostenbrink

Computational Medicinal Chemistry and Toxicology
Department of Pharmacochemistry
Vrije Universiteit                                  Tel: + 31 20 5987606
De Boelelaan 1083 P 262                             Fax: + 31 20 5987610
NL-1081 HV Amsterdam
The Netherlands                          e-mail: c.oostenbrink at few.vu.nl

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