[Chimera-users] modeling non-standard amino acids

Elaine Meng meng at cgl.ucsf.edu
Tue Aug 14 11:20:00 PDT 2007

Hi Daniel,
Chimera does not predict changes in a molecule's conformational  
ensemble resulting from mutations or other chemical modifications.   
For a very constrained structure, it might be possible to get a  
reasonable result by simply making the modification (see Build  
Structure in Chimera) and minimizing (Minimize Structure).

However, it sounds like your structure has several rotatable bonds,  
so prediction is not straightforward.  In that case, Chimera could be  
used to build in the initial change, but then figuring out what will  
happen to the molecule's conformational space is a different story,  
especially in a solvated environment or in complex with another  
molecule.  Attempts to do this fall in to two main categories:

(1) based on inspection of how things look after the chemical change  
(for example, now atoms are clashing, or conversely, a new hydrogen  
bond is formed) the user applies his own chemical intuition as to  
what the downstream effects could be (for example, local unfolding,  
side chain rotates away, ligand no longer binds, etc.).  This can be  
aided by the Chimera tools FindHBond and Find Clashes/Contacts, and  
you can rotate bonds interactively (see Adjust Torsions).

(2) more intensive calculations are performed with another program -  
say molecular dynamics in solvent and possibly in complex with a  
binding partner.  This is also done with the unmodified structure.   
Then the trajectories or conformational ensembles are compared.  Or,  
you could perform a free energy calculation perturbing one structure  
to another. I don't have a specific example, but many published  
papers describe similar work, looking at protein mutations or  
comparing drug/ligand affinities.  Chimera has tools for viewing and  
analyzing conformational ensembles (see the MD Movie tool) but not  
for calculating them in the first place.

I hope this helps,
Elaine C. Meng, Ph.D.                          meng at cgl.ucsf.edu
UCSF Computer Graphics Lab and Babbitt Lab
Department of Pharmaceutical Chemistry
University of California, San Francisco

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