[RASMB] k_off rate

[Allen Minton]

Prof Halford is correct in the general case.  I 
should have limited my remarks to kinetics of 
association at high ionic strength.  Here is an 
extract from Vijayakumar et al (1998) J. Mol. Biol 278: 1015-24:

"Before two proteins associate to form a complex, 
they have to find the proper relative orientation 
by translational and rotational diffusion. The 
orientational constraints will severely limit the 
rate of association. For example, for two 
proteins A and B modeled as spheres with closest 
approach distance R and relative translational 
diffusion constant D, “reactive” patches spanned 
by polar angles in (0, ðA) and (0, ðB) will 
reduce the diffusion-controlled association rate 
constant from the Smoluchowski result 4ðDR 
[Smoluchowski 1917] by a factor of ðAðB(ðA + 
ðB)/8 [Berg 1985 and Zhou 1993]. For ðA = ðB = 
3°, the resulting association rate constant is 
ca. 10^5 M^-1s^-1 which is roughly the magnitude 
of association rate constants observed for a 
number of protein complexes at extremely high 
ionic strengths [Stone et al 1989, Eltis et al 
1991, Schreiber and Fersht 1993, Schreiber and 
Fersht 1996, Wallis et al 1995 and Wendt et al 
1997]. At low ionic strengths, these protein 
complexes are found to be formed three to four 
orders of magnitude faster, indicating the effect 
of electrostatic interactions between associating proteins."

I apologize for any confusion.

Allen Minton



At 10:09 AM 4/7/2008, SE Halford, Biochemistry wrote:
>Sorry, but I disagree strongly with Allen 
>Minton's assertion that protein-protein 
>association rates have "very similar bimolecular 
>association rate constants (say within a factor 
>of 3 or so).  I seem to remember something on the order of 10^5 mol^-1 sec^-1".
>The protein-protein association rates reported 
>in the literature vary from 10^10 M^-1.s^-1 down 
>to around 10^4 M^-1.s^-1.  The high numbers are 
>almost all measured in low salt buffers, 
>conditions where electrostatic effects overwhelm 
>the "Smoluchowski limit" of around 10^8 
>M^-1.s^-1, and when the same protein-protein 
>interaction is measured in buffer containing 
>~250 mM NaCl, the rate falls to ~10^8 M^-1.s^-1, 
>somewhere close to the "Smoluchowski limit".
>So any assumption about the association rate 
>constant could easily be out by a factor of 
>10^4, which in turn gives you a 10^4 error in calculating the koff from the Kd!
>Steve Halford
>----------------------
>Professor Stephen E. Halford FRS
>Department of Biochemistry,
>School Of Medical Sciences,
>University of Bristol,
>University Walk,
>Bristol BS8 1TD, UK.
>tel: +44-(0)117-331-2156 - NB, new phone and new FAX number
>FAX: +44-(0)117-331-2168
>E-mail: s.halford at bristol.ac.uk
>
>--On 07 April 2008 08:20 -0400 Allen Minton <minton at helix.nih.gov> wrote:
>
>>If memory serves, many if not most protein association reactions have
>>very similar bimolecular association rate constants (say within a factor
>>of 3 or so).  I seem to remember something on the order of 10^5 mol^-1
>>sec^-1, but I'm not sure of that, you'd better look it up.  (Note: this
>>is orders of magnitude smaller than the upper limit calculated according
>>to Smoluchowski, which does not take into account the orientational
>>constraints applying to a specific association that greatly increase the
>>entropic barrier to complex formation.)  Therefore, given the equilibrium
>>dissociation constant you should be able to estimate the dissociation
>>rate constant to within this level of uncertainty.
>>
>>Diffusion coefficients are irrelevant.
>>
>>Allen Minton
>>
>>
>>At 07:59 PM 4/5/2008, Wenta Nikola wrote:
>>
>>Content-class: urn:content-classes:message
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>>
>>Dear Colleagues!
>>In order to make my question more precise, I want to to calculate the
>>theoretically diffusion-controlled maximum possible k_off rate of a given
>>dimer based it's kD (from SE run), in combination with a calculated
>>diffusion coefficient for monomer and dimer by HydroPro.
>>If anyone had any suggestions how to calculate that k_off rate, I would
>>be very grateful.
>>Niko
>>
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