Hello, My name is Daniel Wendt and I work for Biomarin Pharmaceuticals in Novato, Ca. I'm trying to use Chimera's modeling software to predict structural changes that are imparted on my 22 amino acid peptide by the insertion of two non-standard changes to the peptide bond. In one case, I am adding a methyl group to the backbone amide bond. In another case, I'm removing a carbonyl from the backbone amide bond. This peptide then needs to be cyclized by the formation of a intra-disulfide bond. I do have x-ray crystal structure data of my cyclized peptide bound to one of its receptors. Do you know how one goes about doing this? Do you have any references that might help? Thank you in advance! Daniel Wendt Senior Scientist BioMarin Pharmaceutical Novato, Ca 94949 (415) 506-6131 This message is intended only for the confidential use of the intended recipient(s). If you have received this communication in error, please notify the sender by reply e-mail, and delete the original message and any attachments. Any unauthorized disclosure, copying, or distribution of this message (including the attachments), or the taking of any action based on it, is strictly prohibited.
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). http://www.cgl.ucsf.edu/chimera/docs/ContributedSoftware/editing/ editing.html http://www.cgl.ucsf.edu/chimera/docs/ContributedSoftware/minimize/ minimize.html 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). http://www.cgl.ucsf.edu/chimera/docs/ContributedSoftware/findhbond/ findhbond.html http://www.cgl.ucsf.edu/chimera/docs/ContributedSoftware/findclash/ findclash.html http://www.cgl.ucsf.edu/chimera/docs/ContributedSoftware/ structuremeas/structuremeas.html#adjust (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. http://www.cgl.ucsf.edu/chimera/docs/ContributedSoftware/movie/ framemovie.html http://www.cgl.ucsf.edu/chimera/docs/UsersGuide/tutorials/ ensembles2.html I hope this helps, Elaine ----- Elaine C. Meng, Ph.D. meng@cgl.ucsf.edu UCSF Computer Graphics Lab and Babbitt Lab Department of Pharmaceutical Chemistry University of California, San Francisco http://www.cgl.ucsf.edu/home/meng/index.html
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Dan Wendt -
Elaine Meng