Subject: CCL: Salt bridges, H-bonds, aromatic stacking in MD?

From: Nick Glover <[email-masked]>
Date: Thu, 12 Feb 1998 11:33:40 -0800

CCLers:

I am looking at the interaction of a bound peptide and a target enzyme
with EM and MD simulations. The peptide is docked into the active site, 
and lies, extended, across the protein, plugging a 'hole'
on the surface of the protein.  I have three queries:

---------------

Q1: Salt bridge...

My major concern is that I have noticed that a salt-bridge between a 
surface Arg on the protein and a bound peptide Asp residue lengthens 
from ~4.0 ang. when docked to > 6.0 ang. during the MD portion of an 
EM/MD run.  It seems to fluctuate by about 1 ang., but over 100 ps 
doesn't shorten to ~4.0 ang. again.  

The system is in a large solvated sphere, and calculations are run on 
Discover 95 with CVFF using the default water model.  

As per advice from MSI, the cutoffs are set thus 
(i.e. double cutoffs, no switching function):

       cutoff=13.00
       cutdis=12.00
       swtdis=0
       cutof2=15.00
       cutds2=14.00
       swtds2=0 

Is this observation considered 'normal' given the conditions of the 
calculations, or should I be concerned? 

-------------

Q2: Intermolecular hydrogen bonds...

Similar to Q1, I also see certain intermolecular H-bonds lengthen 
to > 4.0 ang. (acceptor - donor) during MD simulations, and fluctuate 
about this longer distance (i.e. 3.5 - 4.5 ang).

Again, is this considered 'normal' given the conditions of the
calculation, or should I be concerned?

-------------

Q3: Aromatic stacking...

Can anybody indicate how successful the CVFF forcefield is at simulating
aromatic-aromatic stacking interactions?  I notice that phenyl rings in 
the active site pocket of the enzyme re-orient with respect to ligand,
and appear to adopt 'favourable' edge-on, tilted-T, etc. orientations,
depending on the ligand.

How 'realistic' (within context) are these observations likely to be?

-------------

Can anybody offer any insights into these phenomena?
Thanks in advance,

Nick

____

Nick Glover
Department of Chemistry
Simon Fraser University
8888 University Drive
Burnaby, BC
V5A 1S6
Canada
 
Tel: (604) 291-4531
Fax: (604) 291-3765

email: [email-masked]