Wednesday, April 2, 2008

We have a new integrin ectodomain structure with two molecules in the asymmetric unit. There is a small amount of breathing at what we call the headpiece-tailpiece interface when the two molecules are compared. This is very important to some molecular dynamic simulations that we are doing. The movement between the two molecules is small, a few degrees, but involves large units of the molecule. We would like to use the morph server to extrapolate, rather than interpolate, this motion. I have looked at your description of frodo lite and this seems a good approach. So, following up our meeting at Yale, we would appreciate some help with this.

By "extrapolate" I believe you mean that you want to predict an unknown conformation from one or two known ones. FRODA can in fact be run in "undirected" mode and this will sample the accessible phase space consistent with sterics and the hydrogen bonding pattern. However it does not pick out the desired conformer from the large number of generated conformers. Certain assumptions are also made about the hydrogen bonding pattern which may result in the desired conformation not being present at all in the generated ensemble.

Instead of FRODA, perhaps you want to try our soon to be announced motion prediction tool, the Conformation Explorer. It is specifically designed to predict the motion of domains. Domains are often too large and slow moving to be dynamically characterized by MD. Further complicating matters, the motions are stochastic and the MD force fields are far from perfect; therefore the motion may not be observed even when the trajectory has been computed for a period of time experimentally
known to be sufficient. We have been successful in predicting large scale domain hinge bending motions for five proteins, including biotin carboxylase, glutamine binding protein, and MurA.

We do need to know something about the conformation which is to be predicted, however, in order to pick the right conformer out of the ensemble. If it binds a small ligand, for instance, we can find the holo structure given the apo by computing stability, free energy of ligand binding, gyration radius, and other quantities. Your use of the word "extrapolate" suggests you may have some geometric information about the target conformer which we can use.

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