Analysis of the equilibrium and kinetics of the ankyrin repeat protein myotrophin

Abstract

We apply the Wako-Saito-Muñoz-Eaton model to the study of Myotrophin, a small ankyrin repeat protein, whose folding equilibrium and kinetics have been recently characterized experimentally. The model, which is a native-centric with binary variables, provides a finer microscopic detail than the Ising model, that has been recently applied to some different repeat proteins, while being still amenable for an exact solution. In partial agreement with the experiments, our results reveal a weakly three-state equilibrium and a two-state-like kinetics of the wild type protein despite the presence of a non-trivial free-energy profile. These features appears to be related to a careful "design" of the free-energy landscape, so that mutations can alter this picture, stabilizing some intermediates and changing the position of the rate-limiting step. Also the experimental findings of two alternative pathways, an N-terminal and a C-terminal one, are qualitatively confirmed, even if the variations in the rates upon the experimental mutations cannot be quantitatively reproduced. Interestingly, folding and unfolding pathway appear to be different, even if closely related: a property that is not generally considered in the phenomenological interpretation of the experimental data.

A Disorder-Induced Domino-Like Destabilization Mechanism Governs the Folding and Functional Dynamics of the Repeat Protein IκBα

“…Here we address these issues by employing the structure-based Ising-like statistical mechanical Wako-Saitô-Muñoz-Eaton model [16]–[18] (WSME) with electrostatics [19] and solvation terms [19], [20] that has a higher level of resolution and predictive capability [19], [21] compared to other Ising-like studies on repeat proteins [22]–[27]. We predict in a semi-quantitative fashion several details of the landscape and show how the lack of structure in a single repeat can have a dramatic effect on the resulting landscape with implications on extending the functional repertoire of disordered regions.…”

Thermodynamics of protein folding using a modified Wako-Saitô-Muñoz-Eaton model

“…It is worth noting that more complex multistate models, based on the generalization of the classical Potts model [19,26], can also be employed, though rare so far, to study protein folding [27,28]. Among the above-mentioned models, the Wako-Saitô-Muñoz-Eaton (WSME) model has been applied to study the folding of many proteins [6,7,18,29,30,33] and RNA molecules [31,32]. The WSME model is a topology-based model in which a protein state is represented topologically by {x 1 , x 2 , · · · , x i , · · · x N } ; x i is a binary variable and x i = 1 and x i = 0 indicate, respectively, the folded (native) or unfolded state at the i th local peptide bond.…”

Mapping the Topography of a Protein Energy Landscape

“…The folding and function of repeat proteins have been studied by both experiment and simulation [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] , and they have been found to possess certain features that distinguish them from the more commonly studied globular proteins and that arise from the symmetry inherent in their structures and the absence of long-range interactions. In particular, the modularity of repeat proteins leads to relatively easy dissection of their biophysical properties and consequently they are highly amenable to redesign -of their thermodynamic stability, folding mechanisms and molecular recognition.…”