Conformational Proofreading: The Impact of Conformational Changes on the Specificity of Molecular Recognition

Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
PLoS ONE (Impact Factor: 3.23). 02/2007; 2(5):e468. DOI: 10.1371/journal.pone.0000468
Source: PubMed


To perform recognition, molecules must locate and specifically bind their targets within a noisy biochemical environment with many look-alikes. Molecular recognition processes, especially the induced-fit mechanism, are known to involve conformational changes. This raises a basic question: Does molecular recognition gain any advantage by such conformational changes? By introducing a simple statistical-mechanics approach, we study the effect of conformation and flexibility on the quality of recognition processes. Our model relates specificity to the conformation of the participant molecules and thus suggests a possible answer: Optimal specificity is achieved when the ligand is slightly off target; that is, a conformational mismatch between the ligand and its main target improves the selectivity of the process. This indicates that deformations upon binding serve as a conformational proofreading mechanism, which may be selected for via evolution.

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Available from: Tsvi Tlusty,
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    • "A number of protein structures available both in free and complex forms in the Protein Data Bank (PDB) paves ways for elaborate analysis of secondary structure conformation switching in protein–protein complexes (Goh, Milburn, & Gerstein, 2004). Conformation change upon complex formation serves as a proofreading mechanism imparting specificity and selectivity for the binding partners in a noisy environment of several competing targets (Savir & Tlusty, 2007). Betts and Sternberg (1999) have studied the conformation changes on complex formation for 39 protein– protein complexes from their corresponding unbound structures. "
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    ABSTRACT: Conformation switching in protein-protein complexes is considered important for the molecular recognition process. Overall analysis of 123 protein-protein complexes in a benchmark dataset showed that 6.8% of residues switched over their secondary structure conformation upon complex formation. Amino acid residue wise preference for conformation change has been analyzed in binding and nonbinding site residues separately. In this analysis, residues such as Ser, Leu, Glu and Lys had higher frequency of secondary structural conformation change. The change of helix to coil and sheet to coil conformation and vice versa has been observed frequently whereas the conformation change of helix to extended sheet occurred rarely in the studied complexes. Influence of conformation change towards the N and C terminal on either side of the binding site residues has been analyzed. Further, analysis on φ and ψ angle variation, conservation, stability and solvent accessibility have been performed on binding site residues. Knowledge obtained from the present study could be effectively employed in the protein-protein modelling and docking studies.
    Journal of biomolecular Structure & Dynamics 05/2015; DOI:10.1080/07391102.2015.1050695 · 2.92 Impact Factor
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    • "Investing deformation energy to enhance discrimination appears as a general strategy of molecular recognition systems. This strategy, termed conformational proofreading (Savir and Tlusty, 2007, 2008, 2009, 2010), provides a concrete underlying mechanism, which explains how these deformations are utilized to achieve optimal decoding landscape. Conformational proofreading was demonstrated in the specific case of homologous search (Savir and Tlusty, 2010; De Vlaminck et al., 2012) for a specific linear form of fitness function (weighted difference). "
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    ABSTRACT: The ribosome is a complex molecular machine that, in order to synthesize proteins, has to decode mRNAs by pairing their codons with matching tRNAs. Decoding is a major determinant of fitness and requires accurate and fast selection of correct tRNAs among many similar competitors. However, it is unclear whether the modern ribosome, and in particular its large conformational changes during decoding, are the outcome of adaptation to its task as a decoder or the result of other constraints. Here, we derive the energy landscape that provides optimal discrimination between competing substrates and thereby optimal tRNA decoding. We show that the measured landscape of the prokaryotic ribosome is sculpted in this way. This model suggests that conformational changes of the ribosome and tRNA during decoding are means to obtain an optimal decoder. Our analysis puts forward a generic mechanism that may be utilized broadly by molecular recognition systems.
    Cell 04/2013; 153(2):471-9. DOI:10.1016/j.cell.2013.03.032 · 32.24 Impact Factor
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    • "The ligands that bind and activate these receptors include hormones, neurotransmitters, light-sensitive substances, odorous substances, and pheromones; thus, these ligands vary in size from small molecules and peptides to proteins (King et al., 2003; Filmore, 2004). It is believed that many chemical reactions (including those involved in the transmission of information) utilize the " lock and key " principle (or " hand-glove " , e.g., Savir and Tlusty, 2007). This principle assumes that the shape of one molecule corresponds exactly to the shape of the other molecule. "
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    ABSTRACT: The intracellular channel of information transmission was analyzed from the point of view of complexity. The most important steps in the transfer of information within a cell are the folding, transport and recognition of proteins. It was shown that the large number of conformational degrees of freedom that proteins possess can paradoxically lead to an information channel with an exponentially small capacity. To resolve this paradox, a model, which assumes a quantum collective behavior of biologically important molecules, was proposed. Experiments to test the quantum nature of the intracellular transfer of information were also proposed.
    Bio Systems 02/2013; 111(3). DOI:10.1016/j.biosystems.2013.02.005 · 1.55 Impact Factor
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