Site-Specific Thermodynamics:  Understanding Cooperativity in Molecular Recognition

Di, Enrico

doi:10.1021/cr960135g

Cited by 85 publications

(124 citation statements)

References 150 publications

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“…One such effect is cooperativity, which plays a functional role in a number of macromolecular activities, including recognition and binding (Di Cera, 1998b). First introduced by Wyman (Wyman, 1948;Wyman and Gill, 1990), the concept of cooperativity represents an interdependence of two or more different groups in a system causing a higher binding affinity than would be expected from summing the association energies of the individual parts (nonadditivity).…”

Section: Introductionmentioning

confidence: 99%

A study of collective atomic fluctuations and cooperativity in the U1A–RNA complex based on molecular dynamics simulations

Kormos

Baranger

Beveridge

2007

Journal of Structural Biology

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Cooperative interactions play an important role in recognition and binding in macromolecular systems. In this study, we find that cross-correlated fluctuations can be used to identify cooperative networks in a protein-RNA system. The dynamics of the RRM-containing protein U1A-stem loop 2 RNA complex have been calculated theoretically from a 10 ns molecular dynamics (MD) simulation. The simulation was analyzed by calculating the covariance matrix of all atomic fluctuations. These matrix elements are then presented in the form of a two-dimensional grid, which displays fluctuations on a per-residue basis. The results indicate the presence of strong, selective cross-correlated fluctuations throughout the RRM in U1A-RNA, which correspond well with the results from a statistical covariance analysis of 330 aligned RRM sequences and previous biophysical studies in which a multiplicity of cooperative networks have been reported. Moreover, the MD results indicate that the various networks identified in separate individual experiments are fluctuationally correlated into a hyper-network encompassing most of the RRM. This method has significant implications as a predictive tool regarding cooperativity in the protein-nucleic acid recognition process.

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Section: Introductionmentioning

confidence: 99%

A study of collective atomic fluctuations and cooperativity in the U1A–RNA complex based on molecular dynamics simulations

Kormos

Baranger

Beveridge

2007

Journal of Structural Biology

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“…Notably, the four furin alanine loop mutants showed similar large losses in reactivity with the dual chimera that reflected synergistic effects of the individual serpin B8 substitutions in the chimera except for the 298 -300 loop mutant whose reactivity losses reflected additive effects of the individual substitutions. This suggested that interactions among the furin(298 -300) loop, the serpin primed RCL sequence, and the strand 3C exosite are strongly coupled and that this coupling is lost by mutating the furin loop to alanines (30,31). This conclusion is supported by the finding that the extent of coupling was dependent on the furin(298 -300) loop sequence with the wild-type sequence showing the largest coupling and the PC5 sequence showing no coupling.…”

Section: Discussionmentioning

confidence: 89%

Identification of Serpin Determinants of Specificity and Selectivity for Furin Inhibition through Studies of α1PDX (α1-Protease Inhibitor Portland)-Serpin B8 and Furin Active-site Loop Chimeras

Izaguirre

Lima

et al. 2013

Journal of Biological Chemistry

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Background: ␣ 1 -Protease inhibitor Portland (␣ 1 PDX) and serpin B8 are proprotein convertase (PC) inhibitors whose specificity and selectivity for PCs are not understood. Results: ␣ 1 PDX-serpin B8 and furin-PC chimeras revealed new serpin and protease (re)active-site and exosite determinants of reactivity. Conclusion: ␣ 1 PDX reactive-site and exosite determinants may be exploited for engineering specificity and selectivity for inhibiting PCs. Significance: Specific PC inhibitors will advance understanding of PC function and therapeutics.

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“…In this approach, each amino acid in a primary sequence is individually replaced by the amino acid alanine, and the effect of this mutation is tested in a functional assay. In this way, it is possible to eliminate all side chain interactions, except for the C␤ atom, without altering the main chain conformation or the insertion of steric effects (12)(13)(14). Alanine is a common natural amino acid in all kinds of secondary structures, including TMDs (12).…”

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confidence: 99%

Membrane Anchoring and Interaction between Transmembrane Domains are Crucial for K+ Channel Function

Gebhardt¹,

Hoffgaard

Hamacher

et al. 2011

Journal of Biological Chemistry

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The small viral channel Kcv is a Kir-like K ؉ channel of only 94 amino acids. With this simple structure, the tetramer of Kcv represents the pore module of all complex K ؉ channels. To examine the structural contribution of the transmembrane domains (TMDs) to channel function, we performed Ala scanning mutagenesis of the two domains and tested the functionality of the mutants in a yeast complementation assay. The data reveal, in combination with computational models, that the upper halves of both TMDs, which face toward the external medium, are rather rigid, whereas the inner parts are more flexible. The rigidity of the outer TMD is conferred by a number of essential aromatic amino acids that face the membrane and probably anchor this domain in the bilayer. The inner TMD is intimately connected with the rigid part of the outer TMD via ⅐⅐⅐ interactions between a pair of aromatic amino acids. This structural principle is conserved within the viral K ؉ channels and also present in Kir2.2, implying a general importance of this architecture for K ؉ channel function.K ϩ channels are transmembrane proteins, which catalyze the selective and regulated flux of potassium ions across membranes. A breakthrough in understanding of structure/function correlates in these important proteins occurred with the highresolution structures determined for several K ϩ channels (1-4). Many functional properties such as selectivity and gating of K ϩ channels are now understood on the basis of the specific architecture of these channel proteins. Still, many aspects of function and regulation cannot be explained only on the basis of the protein structure. The performance of the protein also depends on the lipid environment and on the organization of the protein in this environment. Indeed, there is increasing evidence that many different properties of K ϩ channels are depending on the interaction between the protein and the surrounding host membranes (5-7). As a consequence of this dependence, many amphiphilic drugs, which target ion channels, have dual effects, one effect being directly related to an interaction with the protein and a secondary effect being mediated by modification of the bilayer properties (8).A good model system for understanding the interplay of membrane proteins with the membrane is provided by the viral potassium channel Kcv (9, 10). This Kir-like potassium channel with two transmembrane domains is, with only 94 amino acids, very small. The protein is almost completely embedded in the membrane. Only a small, 15 amino acid-long domain at the N terminus and a short turret domain between the two transmembrane domains stick out of the membrane into aqueous solution (11). It can be assumed that in this arrangement any protein/membrane interaction strongly reflects back on function.Unbiased information on the structural significance of the two transmembrane domains (TMDs) 2 and their importance for channel function can be obtained by an alanine scan of the relevant domains. In this approach, each amino acid in a primary seq...

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Site-Specific Thermodynamics: Understanding Cooperativity in Molecular Recognition

Cited by 85 publications

References 150 publications

A study of collective atomic fluctuations and cooperativity in the U1A–RNA complex based on molecular dynamics simulations

A study of collective atomic fluctuations and cooperativity in the U1A–RNA complex based on molecular dynamics simulations

Identification of Serpin Determinants of Specificity and Selectivity for Furin Inhibition through Studies of α1PDX (α1-Protease Inhibitor Portland)-Serpin B8 and Furin Active-site Loop Chimeras

Membrane Anchoring and Interaction between Transmembrane Domains are Crucial for K+ Channel Function

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