[gmx-users] Bug in free energy calculations in heme-containing systems

[Chris Oostenbrink]

Hello,
An error occurs in free energy calculations (TI) of heme-containing 
systems, even if the heme moiety itself is not involved in the 
perturbation.
In the gromos 43a1 force field, the heme iron atom is coordinated by 
four nitrogen atoms (NA, NB, NC and ND), all in one plane and possibly 
by one histidine Nitrogen, NE2, above this plane. Default force-field 
parameters for the connection between His and Heme are defined in file 
ffG43a1bon.itp, including the N[ABCD] - FE - NE2 angle of type ga_16.
In a simulation of a heme-containing system, the parameters of the 
intraheme N[ABCD] - FE - N[ABCD] angles are of type ga_1 (90 degrees) as 
specified in the topology for state A. However, in the tpr-file 
generated by grompp, these angles get the parameters of ga_16 (115 
degrees) for state B!!

Effect
Unperturbed simulations of such systems are probably unaffected, but as 
soon as a thermodynamic integration calculation is performed two things 
will happen (also if the Heme is not coordinated to a His): 1) The Heme 
group will deform due to increasing angles around the iron, 2) a 
corresponding free energy contribution of about 100 kJ/mol will be added 
to the total free energy difference that is being calculated.

Solution
The reason for all this probably lies in grompp, where the standard 
force-field parameters are incorporated into the system topology, 
resulting in a faulty tpr-file. In the case where the Heme group is not 
coordinated to a His, commenting out the default force-field parameters 
in file ffG43a1bon.itp seems to help. Otherwise, explicitly stating all 
Heme parameters in state B as well may also prevent the error from 
happening.

Chris de Graaf and Chris Oostenbrink

-- 
========================================================================
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
========================================================================