AMBER Archive (2004)

Subject: AMBER: MD & folding

From: bybaker_at_itsa.ucsf.edu
Date: Tue Nov 02 2004 - 01:03:42 CST

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Hello, Amber:

I use molecular dynamic simulation to explore the pH effect on the
protein folding. The purpose is to find out the most flexible regions on
my target protein. The runs were set up at two conditions: pH 7.0 and pH
2.0. For the run at pH 2.0, all Glu, Asp and His residues were changed to
their protonation states. For the run at pH 7.0, no change was made on
these residues. When I analysis the results from 1 ns simulations,
something came out very strange. The RSMD curve of pH 2.0 is at the
similar level as that of pH 7.0. The RMSD values at pH 2.0 are even
smaller that those at pH 7.0. The mean value of RSMD at pH 2.0 is 1.41
+_ 0.21 Å. The mean of RSMD at pH 7.0 is 1.63+_ 0.32 Å.

I also did the trajectories analysis. I selected the frames from the time
points with the lowest energy levels, saved the individual frames and
clustered them together. I didn’t see significant changes on the overall
structures. When I examined atom distances of some target salt-bridges
in the protein model, I observed that some, but not all, had larger
values at pH 2.0 than that at pH 7.0.

From the literatures, many indicated that significant changes on the
protein structures were observed with MD simulation under certain
conditions, such as high temperature and low pHs. From CD studies, the
protein I used for the MD simulation was observed losing its tertiary
structure at acid conditions (pH 2.0 – 4.5), but some of secondary
structures remained. A ‘molten structure’ has been proposed for the
conformation of this protein at low pH conditions.

The results from my MD simulations showed that the protein is quite
stable at the low pH condition. This is controversial to the results from
experimental studies. I am wandering if I set my MD running conditions
reasonable or not. I use AMBER7. The protein models were solvated with
WATERBOX 216 with 10 Å distance. The systems were not neutralized. At pH
7.0, the overall charge of the model is +2.0. At pH 4.0, the overall
charge is +32. I use ff94 force filed plus the modified
frcmod.mod_phipsi.1 from Amber website. I have included my MD input files
and the RSMD plots as attachments.

Thank you for your advices and comments.

Regards

Bo


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