[gmx-users] Protein almost detaching from the micellar core

[soumadwip ghosh]

Hi all,

I am simulating a membrane protein embedded in a detegent micelle
(didodecyl maltoside DDM micelle). I am using total 167 number of DDM
monomers and 17 cholesterol hemisuccinate (CHS) molecules for mimicking
experimental conditions under which it has been attempted to be
crystallized. Thus the protein I have is not a crystal structure its a
homology model based on a close analog. The experimental aggregation number
of DDM forming a micelle is ~145 and I am taking 167 for building my
initial micelle followed by replacing some of them randomly with CHS
molecules. I did 50 ns of NPT equilibration using gradual release of
position restraints on all the components of the system. My production run
is 300 ns long. I am using gromos54a7 force field and the united-atom
formalism. I am observing that the protein is detached from the micellar
core and comes near the periphery of the preformed micelle after 300 ns.
The protein is exposed to solvent. Now I dont have any doubt about my
equilibration but am I getting something weird? I dont know if my initial
DDM model was erroneous. Have someone else come across such thing? The
model has been used frequently in our research group(
pubs.acs.org/doi/abs/10.1021/jacs.6b08742) and for crystal structures have
been shown located near the core of the micelle. The other part of the
story is the protein I am studying is experimentally known
to be prone to aggregation. So I dont know whether I should be happy or sad
about the results. One possible thing may be an inadequate number of DDM
monomers to begin with but then how for a well-
resolved crystal structure the protein-detergent complex (PDC) with the
identical initial DDM construct is very stable? Is the protein going
outside since due to its inherent tendency to aggregate or this is
an artifact of my simulation which was wrong to begin with. In that case, I
have to alter to monomers to construct the pre-formed micelle.

I looked up literature and could not see anything similar. It seems like
the PDC is quite stable over time as suggested by some of references from
Prof Mark Sansom's eminent research group.

I will be obliged if someone guides me a little bit in this regard. Any
literature or material which include such observation will be really
helpful in understanding whats going on.

Thanks in advance
Soumadwip Ghosh
Post Doctoral Research Associate
Prof. Vaidehi Nagarajan's Research Group
City of Hope Cancer Research Center
Duarte, CA
United States