Dynamics of Protein-Protein Docking: Cytochrome c and Cytochrome c Peroxidase Revisited

Abstract

The dynamics of the docking step in the electron transfer reaction between yeast cytochrome c peroxidase and iso-1-cytochrome c has been studied using the Brownian dynamics method. In particular we have calculated the bimolecular rate constant at which a specific complex, the xray crystalline complex, can form in solution by translational and rotational diffusion in a field of force. Complexation criteria have been assessed based on the simultaneous alignment of three atom-atom contacts, as well as alternative criteria. The proteins are able to align one or two contacts at remarkably high rates, in fact, at rates approaching the diffusion-controlled limit for two spheres reactive over their entire surfaces. Three contacts may align, and hence the specific complex may dock, at rates on the order of 10(8) M(-1) s(-1), which is quite representative of the experimental association rate constant for ET-competent complex(es). The formation of the specific complex is strongly influenced by the favorable electrostatic interaction between these proteins. It is striking that a specific protein-protein complex can form within one order of magnitude as fast as two spherical proteins can touch at any orientation. It remains plausible that the high ET tunneling rate in this system can take place through a single highly favorable specific complex using a single high efficiency pathway. Still the contribution from a nonspecific set of complexes is not ruled out, particularly considering the marginal reproduction of the ionic strength dependence in the formation of the xray complex.

Brownian dynamics simulations of glycolytic enzyme subsets with F‐actin

“…Using the atomic coordinates for each protein, the charges of the titratable amino acids were calculated and assigned by applying the Tanford–Kirkwood method with static accessibility modification27–30 using the MacroDox charge set31 at pH 7.0, ionic strength 0.05 M , and a temperature of 298 K. The MacroDox charge set used the original CHARMm force field with the united atom method32; the united atom method was chosen because of the size of the F‐actin hexamer (17,616 heavy atoms). This force field has been successfully used in a variety of BD simulations of protein–protein interactions including a review by Elcock, Sept, and McCammon,33 cytochrome c–cytochrome c peroxidase,34, 35 plastocyanin–cytochrome f,36 Zn‐myoglobin–cytochrome b 5 ,37 scorpion toxin Lq2–potassium ion channel,38 and simulations of the active site lid in rhizomucor miehei lipase 39…”

Adrenodoxin: Structure, stability, and electron transfer properties

“…The influence of dipole moment changes on the redox potential and on the docking kinetics should be investigated experimentally by mutations of residues not included in interaction or ET processes but influencing the dipole moment. However, it might also be possible that dipoles do not play a significant role in the docking process, but the partner proteins search each other in a semiclosed sphere and then optimize charge and nonpolar interactions 66. Elimination of a positive charge at the solvent‐exposed position 14 (Adx(4‐108)/ R14A mutant), which is far removed from the iron‐sulfur center, slightly increased the redox potential by 12 mV (Table II).…”

Brownian dynamics of interactions between aldolase mutants and F‐actin

“…The MacroDox charge set uses the original CHARMm force field with the united atom method (Brooks et al, 1983); the united atom method was chosen because of the size of the proteins (the F-actin hexamer contained 17,616 heavy atoms and the aldolase tetramer contained 11,029 heavy atoms). This force field has been successfully used in a variety of BD simulations of protein-protein interactions including a review by Elcock et al (2001), cytochrome c-cytochrome c peroxidase (Northrup et al, 1987;Castro et al, 1998), plastocyanincytochrome f (Pearson and Gross, 1998), scorpion toxin Lq2potassium ion channel (Cui et al, 2001), and simulations of the active site lid in rhizomucor miehei lipase (Peters et al, 1996). The charges of rabbit muscle actin, its mutants, rabbit aldolase and its mutants can be found in Tables 1-3. Following charge assignments, the electrostatic fields around the proteins were determined by numerically solving the linearized Poisson-Boltzmann equation as implemented in the program MacroDox (algorithm overviewed in Northrup et al, 1997a,b).…”