QUESTIONS: alpha-helix "signals" in proteins

Tom Gladd ntgladd at langmuir.EECS.Berkeley.EDU
Mon Jul 11 22:37:14 EST 1994

I have followed this discussion with interest.   I hope I can impose on 
the group to make an argument from a physicist’s perspective.  I won’t 
argue “kinetic” versus “thermodynamic” but will claim the process of 
protein folding is indeed path dependent but that this path dependence 
is not inconsistent with observations.

Given some initial unfolded protein state, the various components will 
feel unbalanced electrical forces and dynamically respond, tracing out 
some path in the multidimensional phase space whose coordinates 
characterize the protein.  As the protein system moves along this path, 
individual components will be lose or gain kinetic energy in response to 
the temporally changing forces they experience (alternatively, in 
response to the steepness of the potential energy surfaces they are 
traversing).  When the protein finds a point in phase space about which 
the variation of all  its variables become periodic it can be said to be 
metastable.  Not only has the protein found a local energy minimum, but 
each of its components is rocking or rotating back and forth  in its own 
potential well.  I say metastable because such a system would 
constitute a highly complex nonlinear oscillator in which resonances 
could develop that would knock one or more components out of their 
local well and thus destabilize the system.  A complicated physical 
system like a protein has many local energy minima and the particular 
minimum (located at a point in phase space) in which the hypothetical 
protein came to metastability represents the end point of the path it took 
through phase space.  A protein with different initial conditions might 
well have followed a different path and metastabilized in a different local 

So what does this dynamical picture have to do with the observations 
that most proteins (but, not all) fold to the same “native” state.  To 
explain these observations I would say that such proteins are 
characterized by a minimum energy state (not necessarily global) with 
two features - 1) much  steeper walls than other local energy minima 
(much more stable), and most important 2) a much greater basin of 
attraction than the other local minima (much more accessible).  By the 
latter, I mean that the large majority of initial states follow phase space 
trajectories that lead to this minimum.  A two dimension example of such 
a potential surface would be an empty swimming pool with a few pots 
and pans scattered on the bottom.  Where a given rain drop ends up 
certainly depends on the path it takes, but most of them will go down 
the drain at the bottom of the pool.  For most proteins, then, the 
“native” state corresponds to a local energy minimum with such a large 
basin of attraction that almost any initial conditions will follow a path to 
that minimum.  Under such circumstances the native state appears to be 
path independent.

I’m not sure what this picture means for a predictive theory of folding  -- 
unless, perhaps, one could mathematically demonstrate that certain 
sequences of amino acids are likely to lead to large phase space 
attraction basins for certain secondary structures.

My two cents.  I apologize if these arguments already exist in the literature.

N. T. Gladd 
Berkeley Research Associates
ntgladd at langmuir.eecs.berkeley.edu

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