Subject: [Q] Histogram method

From: [email-masked]
Date: Sat, 23 Jan 1999 18:16:17 -0500 (EST)

I've come across a few papers on computational protein models that
claim to use the so-called histogram method to estimate free energies
of folding, but I don't see how they could have done this, except for
cases much more trivial than those reported.  It seems to me that to
apply the histogram method, it would be necessary to run a simulation
that sampled both the folded *and* the unfolded states reasonably well
(so that the population histograms collected had any chance of
approximating the real relative probabilities of the two macrostates).
This means running the simulation at temperatures close to the folding
transition temperature, Tf.  But, except for very short chains (N <
75) or very streamlined models (cubic lattice models),
folding/unfolding events become so rare as T approaches Tf, that it
would take weeks or even months to collect the data for each
application of this method.  Is this so?

I hope I'm wrong in this assessment, and that someone would be kind
enough to clear up my confusion.  Specifically, how is it possible to
use the histogram method to estimate free energies of folding
*without* collecting many folding/unfolding events near Tf?

Thanks in advance,

KJ