Conformational selection and induced fit mechanism underlie specificity in noncovalent interactions with ubiquitin

Abstract

Noncovalent binding interactions between proteins are the central physicochemical phenomenon underlying biological signaling and functional control on the molecular level. Here, we perform an extensive structural analysis of a large set of bound and unbound ubiquitin conformers and study the level of residual induced fit after conformational selection in the binding process. We show that the region surrounding the binding site in ubiquitin undergoes conformational changes that are significantly more pronounced compared with the whole molecule on average. We demonstrate that these induced-fit structural adjustments are comparable in magnitude to conformational selection. Our final model of ubiquitin binding blends conformational selection with the subsequent induced fit and provides a quantitative measure of their respective contributions.ubiquitin binding ͉ protein recognition ͉ Kolmogorov-Smirnov test T he picture of protein-protein interactions has, over the decades, evolved from the early lock-and-key hypothesis (1) to the generally accepted and widely applied induced-fit model (2, 3). However, several different systems have recently been shown to follow an alternative paradigm whose central element is the idea of conformational selection (4). Within this paradigm, the conformational change in binding is thought to originate primarily from the conformational diversity of the unbound state (5-15). Simply put, the unbound protein explores the energy landscape, spending most of the time in the lowest energy conformations, but also occupying higher-energy ones, some of which are structurally similar to the bound conformations. In the course of binding, because of favorable interactions with the ligand, these conformers get preferentially selected and the population of protein microstates shifts in the direction of bound conformations (4-15). In a way, induced fit and conformational selection are two extremes of possible mechanisms underlying protein interactions (16): in the former, optimal binding is achieved by specific structural change, whereas in the latter it is brought about through selection from the already present unbound ensemble. The two mechanisms have recently been compared from the perspective of kinetics (17) and the energy landscape theory (18).Some of the earliest-described examples of the conformational selection paradigm are the antibody-antigen interactions where an antibody can be found in different unbound conformations, exhibiting different specificity for different antigens (19)(20)(21)(22). Binding then occurs by a simple selection of those antigens whose epitopes are already in a matching conformation for the paratope. In general, growing support for conformational selection in specific protein-protein interactions is based mainly on finding bound-like conformations of proteins in the respective unbound ensembles of structures (12,14,(23)(24)(25)(26)(27)(28)(29)(30). For example, Gsponer et al. (30) proposed that Ca 2ϩ -bound, ligand-free calmodulin samples the conformational space of ...

Kink turn sRNA folding upon L7Ae binding using molecular dynamics simulations

“…TSE structures can either fold or unfold, and the transition probability (P) will be 50%. To search for the transition state for each simulation system, snapshots along high temperature simulations in every trajectory were clustered into groups 83 through global multidimensional scaling (MDS) analysis 79 on atomic RMSD values. Values between any two snapshots were supposed to be the distances between any two points in a three-dimensional space.…”

“…To pursue this question, conformational changes were quantitatively compared through histograms of RMSD counts for both mechanisms. 79 Relative magnitudes were calculated and shown in Fig. 4.…”

“…This is consistent with the previous work. 79 Same analyses were also conducted on protein L7Ae (listed and shown in Table S1 and Fig. S3, ESI †).…”

Ubiquitin-Dependent Sorting in Endocytosis

“…In addition, Ub exists in different conformations that become apparent when comparing the structures of various UBD:Ub complexes (Lange et al 2008). Thus Ub can dynamically adopt several conformations that can subsequently be captured by UBDs by a variable combination of conformational selection and induced fit (Wlodarski and Zagrovic 2009;Long and Bruschweiler 2011;Peters and de Groot 2012). The weak binding of isolated UBDs forces the cell to apply a number of supportive mechanisms that increase the strength of binding and ensure specific signaling.…”

Structural and Dynamic Insights of the Interaction between Tritrpticin and Micelles: An NMR Study

“…The most accepted theory is that with conformational selection, the dominant bonding process occurs in conjunction with structural adjustment (induced fit) to optimize the interaction (63)(64)(65)(66)(67).…”