CCL: Questions on the protonations of a HIV-1 protease (1aaq)

 Sent to CCL by: Elaine Meng [meng,,cgl.ucsf.edu]
 Hi Guosheng,
This paper may be useful. There is a short discussion of the active site Asp residues in HIV-1 protease (p. 714). 
 Li H, Robertson AD, Jensen JH.
Very fast empirical prediction and rationalization of protein pKa values. 
 Proteins. 2005 Dec 1;61(4):704-21.
 PMID: 16231289
Also, in simulations, people have often protonated one of the active site Asp residues. AMBER, for example, includes an ASH residue that could be used in this case. I don't have a specific reference, but you could just search in PubMed for simulation studies on HIV1PR to see what others have done. 
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 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
On Jan 16, 2006, at 1:17 PM, Guosheng Wu wu_guosheng2002%%yahoo.com wrote: 
 
 Sent to CCL by: Guosheng Wu [wu_guosheng2002[*]yahoo.com]
 Dear listers,
I am puzzled in assigning protonation states for some HIV-1 protease complexes, and 1aaq(pdb code) 
 is a typical complex of many structures.
From this structure, one can see all of the 5 oxygen atoms (from Asp 25 & Asp 125, and ligand OH)
are very close to each other(2.7~3.1), and almost in the same plane. Also each of the Gly 27 is not far away(about 3.3 Angstrom) from the Asp 25, although the angle of H-bond is not very good (the Xray resolution is 2.5 Angstrom, exp. done in 1992; only one water is given, but not close to 
 this part).
Since the OO contact between Asp 25 and Asp 125 is 2.5 Angstrom, which is about the distance of OO in H5O2+ ion(2.4), one would like to assign a proton between them. However, it seems very 
 difficulty to rationalize other polar interactions.
One possible explanation may have something to do with quantum effect, which may lead to some modifications over the hybridization of the ligand Oxygen atom, as well as some of the C-O-H bond angles. Certainly, some kind of minimizations may be able to help on some directions, but it seems to me typical current force field would have trouble for this case.
I wonder if you have done any study on this special complex, or similar cases (actually many pdb structures are like this one). I would really appreciate if you could share some of your insights 
 with me.
 Best regards,
 Guosheng