Subject: Re: CCL:MEAD pKa calculations

From: Don Bashford <[email-masked]>
Date: Sat, 15 Feb 2003 12:37:46 -0800

>>>>> "CUI" == CUI, Guanglei <[email-masked]> writes:

    > Don> My guess is it [the choice of which lysine H to zero] won't
    > Don> make so much difference, but why not try 
    > Don> it all three ways?
    CUI> One of the three is different from the other two. pkint is
    CUI> calculated around 8. Very interesting ...

    CUI> UNK is triclosan. It's neutral. The phenol hydroxyl hydrogen
    CUI> is hydrogen-bonded to the TYR in hydrogen-added crystal
    CUI> structure. The LYS is the only titratable group sticking
    CUI> inside of the protein. From the great impact of hydrogen
    CUI> atoms of the LYS, I guess the same effect could happen to UNK
    CUI> too. 

Okay, my guess (that which H is zeroed doesn't matter) was wrong.  It
sounds like you have potential H-bonding networks involving the
ionizable residues that can have important energetic consequences.
That means, at a minimum, at all protonation microstates, you should
take care to have hydrogen positions that are optimal in terms of
H-bonding networks.  A more rigorous approach is to do calculations
allowing for multiple possible H-positions, and proper statistical
averaging which allows for the correnct arrangements to predominate.
Neither of these things is automatic in MEAD.  You need to look
carefully at the structure, perhaps using molecular mechanics programs
to search for and try out various H-bond arrangments, etc.

For some examples of how we've handled such situations, have a look at
Demchuk et al, Biochem 39:1100 (2000); and Spassov et al, JMB 312:203,
(2001).  In particular, see the Demchuk paper for how we handle charge
parameters for a phenolate group; if a buried negative phenol is a
real possibility, then delocalization of the negative charge is going
to be an important issue.

    CUI> Here's the .g file. All terms are fairly small...

    CUI> 1 1   0.000000e+00
    CUI> 1 2   2.158370e-02
    CUI> 1 3   4.047996e-02
    CUI> 2 1   2.158370e-02
    CUI> 2 2   0.000000e+00
    CUI> 2 3   2.034296e-02
    CUI> 3 1   4.047996e-02
    CUI> 3 2   2.034296e-02
    CUI> 3 3   0.000000e+00

Actually, those are not small at all!  The energy units are your input
charge units squared divided by your imput length units, so typically
protons**2/Ang.  The conversion factor to pK units is about 250, or to
kcal/mole, about 330.  So, for example the interaction between sites 1
and 3 is worth about 10 pK units!

Cheers,
Don