Reduced protein models

Cherfils J, Duquerroy S, Janin J. Protein-protein recognition analyzed by docking simulation. Proteins 1991 11 271-280. Zacharias M. Protein-protein docking with a reduced protein model accounting for side chain flexibility. Protein Sci. 2354 12 1271-1282. 

While molecular dynamics (MD) simulations have proven to be very powerful for studying numerous aspects of protein dynamics and structure [11-13], this technique cannot yet access the millisecond-to-second time-scales required for folding even a small protein. To address this timescale gap, one has to simplify the protein model by reducing the number of degrees of freedom. Such approaches assume that the basic physics could be reproduced in model systems that employ united atoms and effective solvent models. On the basis of recent work, it has become apparent that the crux of the solution to the protein folding problem does not lie in whether a reduced protein model is used, but rather in the development of... 

The lattice models mentioned above were among the first to test the predictions of energy landscape theory as well as to show that many important features in protein folding could be captured by simple physical principles. In other studies, lattice models have been extended to include side-chain elements,side-chain-only models, and diamond, body-centered cubic (bcc) and face-centered cubic (fee) lattices. These models, while maintaining their simplicity and computational tractability, are much more realistic than those discussed above, and will likely provide further insight into the interactions that drive protein folding. For an excellent review on reduced protein models, we refer the reader to Kolinski and Skolnick and the extensive references therein. ... 

This article describes the current state of the art and various applications of modeling techniques to the prediction of the native, biologically active conformation of a protein. This is a very active area of computational biology, and there are a number of excellent reviews of the field. " Here, we focus on the use of simplified or reduced protein models and the insights that they can provide into protein structure prediction and the nature of interactions in globular proteins. 

Reduced Protein Models Using a Lattice Representation... 

Figure 1 Reduced protein model in which Cos are confined to a set of lattice points, but where the side chain centers of mass are de.scribed in a continuous space representation...

Over the last decade, using reduced protein models, considerable progress has been made towards understanding the nature of the protein folding process as well as in the development of techniques to predict low resolution tertiary and in some ca.ses quaternary structure from protein sequence. Becau.se they reduce the number of degrees of freedom, reduced or simplified protein models can address aspects of... 

S. Sun, Reduced representation model of protein structure prediction statistical potential and genetic algorithms. Protein Sci. 2 (1993), 762-785. 

On a lattice, so-called crankshaft moves are trivial implementations of concerted rotations [77]. They have been generalized to the off-lattice case [78] for a simplified protein model. For concerted rotation algorithms that allow conformational changes in the entire stretch, a discrete space of solutions arises when the number of constraints is exactly matched to the available degrees of freedom. The much-cited work by Go and Scheraga [79] formulates the loop-closure problem as a set of algebraic equations for six unknowns reducible... 

The other way to study the "conductivity of protein molecules towards electron tunneling is to investigate the quenching of luminescence of electron-excited simple molecules by redox sites of proteins [95,96]. Experiments of this sort on reduced blue copper proteins have involved electron-excited Ru(II)(bpy)3, Cr(III)(phen)3, and Co(III)(phen)3 as oxidants. The kinetics of these reactions exhibit saturation at protein concentrations of 10 3 M, suggesting that, at high protein concentrations, the excited reagent is bound to reduced protein in an electron transfer precursor complex. Extensive data have been obtained for the reaction of reduced bean plastocyanin Pl(Cu(I)) with Cr(III)(phen)3. To analyze quenching experimental data, a mechanistic model that includes both 1 1 and 2 1 [Pl(Cu(I))/ Cr(III)(phen)3] complexes was considered [96]... 

Meanwhile, Blumberg and Peisach (145) showed that the interaction between a low-spin ferrous atom and an adjacent free radical can give rise to a g= 1.94 EPR signal. Brintzinger, Palmer, and Sands (146) proposed the first two-iron model for the active center of a plant-type ferredoxin. Their model, which consisted of two spin-coupled, low-spin ferric atoms in the oxidized protein and one low-spin ferric and one low-spin ferrous atom in the reduced protein, explained much of the chemical data on the proteins. Later, they (Brintzinger, Palmer, and Sands, (147)) presented EPR data for a compound, bis-hexamethylbenzene, Fe(I), which demonstrated all the properties fo the g= 1.94 signal observed in the ferredoxins. 

The g—1.94 EPR signal of the reduced proteins must be explained by any model for their active site. Using subscript 1 to specify the ferric-iron site and subscript 2 the ferrous-iron site, the spin-coupled model explains this EPR signal in the following way. The electron magnetic... 

Other Mossbauer data which indicate that the model is correct are the measured -values for the low-temperature, reduced-protein spectra. The measured a-values for the ferric iron (Table 6) are close to isotropic with an average value of —17 gauss. Remembering that this a-value is calculated for an electron spin= 1/2 situation, we now recalculate the a-value for the ferric site in terms of the 5/2 spin present at this site. For the ferric site in the spin-coupled model,... 

The protein sequence data in Table 2 show that the cysteine residues in all the proteins occur in identical positions (18, 39, 44, 47, 77) in the sequence. Thus, the ligand field produced by the cysteinyl-sulfur atoms is not likely to be different among these proteins unless there is a difference in protein conformation which causes a displacement in one or more of the cysteinyl sulfur atoms. Note that a displacement of any cysteinyl sulfur atom in the model in Fig. 15 results in rhombic distortion at the iron to which it is ligated. Since, according to the spin-coupled model, this rhombic distortion will manifest itself in the difference between gx and gx for a particular protein, the EPR data in Table 1 provide a measure of the rhombic distortion around the ferrous iron in the reduced proteins. In particular, the g-values of adrenodoxin are axially symmetric while the g-values of spinach ferredoxin show a rhombic distortion. Thus, the observation of Kimura et al. (168) that adrenodoxin and spinach ferredoxin have different protein conformations is consistent with the prediction of the above model. 

A. Kolinski, Protein modeling and structure prediction with a reduced representation. Acta Biochim. Polon. 51, 349-371 (2004)... 

---