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Re: WSN: hidrophobic/Van der Walls interactions energy... (fwd)
Sender: bruce_bush@merck.com (Bruce Bush)
Subject: Re: WSN: hidrophobic/Van der Walls interactions energy...
David Haney (haney@netcom.com) writes re Kahn comment on Hb sickling:
> I apologize if I missed an important part of previous discussion on this
> topic. [...] I have studied
> sickle hemoglobin both in the lab and using computational tools. Yes you can
> demonstrate computationally, the hydrophobic region that is generally
> described by inspecting the fiber structure. However, I think it would be
> difficult to calculate the free energy value for this mutation. You can use
> a program like HINT [...]
>
> In a computational study in which I evaluated the potential energy of various
> residues in the crystal fiber, I found that while the process may be driven
> by hydrophobicity, there are clear electrostatic interaction contributing to
> the stablity of this fiber. Sone of these interactions are in the same area as
> the mutation at Beta Lys 8 which interacts with the proprionate of the heme
> in the adjacent molecule. Clearly additional solvent methods would be a
> benefit, but we must be able to account for salts and solute concentration
> to make free energy predictions based on atomistic parameters. [...]
>
Dr. Haney -- you missed nothing of substance. I just *mentioned* a hypo-
thetical mutation beta6(glu->val). Kahn makes an important point which I
was leaving implicit: one cannot directly compare free-energy changes for
processes that involve different states of aggregation. You raise further
valid general points (how many free-energy methods even try to account for
salt effects? how many computationalists are careful to relate "delta-free-
energies" to a specific solute concentration?) as well as some useful
and intriguing comments about HbS in particular. (So-called "hydrophobic
aggregation" can be strongly depended on electrostatic interactions!)
Perhaps Drs. Haney and Kahn, who are well-versed in HbS aggregation, would
like to lead a discussion 'thread' on this topic. I'll bow out with just
the observation that cooperative aggregation is much more subtle even than
two-state binding in solution.
Regards to you both -- Bruce (bruce_bush@merck.com)