From “fluctuation fit” to “conformational selection”: Evolution, rediscovery, and integration of a concept

Vértessy, Beáta G.; Orosz, Ferenc

doi:10.1002/bies.201000068

Cited by 33 publications

(44 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Structural plasticity in Eph-ephrin recognition has been documented experimentally [59–61]. Qin et al [60] observed that heterogeneous free EphA4 conformations, including both the open and closed loop conformations, already exist before binding to the ephrin ligands, supporting the ‘conformational selection and population shift’ mechanism [1–7]. …”

Section: Discussionmentioning

confidence: 99%

Promiscuous and specific recognition among ephrins and Eph receptors

Dai

Huang

Nussinov

et al. 2014

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

View full text Add to dashboard Cite

Eph-ephrin interactions control the signal transduction between cells and play an important role in carcinogenesis and other diseases. The interactions between Eph receptors and ephrins of the same subclass are promiscuous; there are cross-interactions between some subclasses, but not all. To understand how Eph-ephrin interactions can be both promiscuous and specific, we investigated sixteen energy landscapes of four Eph receptors (A2, A4, B2, and B4) interacting with four ephrin ligands (A1, A2, A5, and B2). We generated conformational ensembles and recognition energy landscapes starting from separated Eph and ephrin molecules and proceeding up to the formation of Eph-ephrin complexes. Analysis of the Eph-Ephrin recognition trajectories and the co-evolution entropy of 400 ligand binding domains of Eph receptor and 241 ephrin ligands identified conserved residues during the recognition process. Our study correctly predicted the promiscuity and specificity of the interactions and provided insights into their recognition. The dynamic conformational changes during Eph-ephrin recognition can be described by progressive conformational selection and population shift events, with two dynamic salt bridges between EphB4 and Ephrin-B2 contributing to the specific recognition. EphA3 cancer-related mutations lowered the binding energies. The specificity is not only controlled by the final stage of the interaction across the protein-protein interface, but also has large contributions from binding kinetics with the help of dynamic intermediates along the pathway from the separated Eph and ephrin to the Eph-ephrin complex.

show abstract

Section: Discussionmentioning

confidence: 99%

Promiscuous and specific recognition among ephrins and Eph receptors

Dai

Huang

Nussinov

et al. 2014

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

View full text Add to dashboard Cite

show abstract

“…347,541 Exclusive induced fit mechanisms have been proposed for some disorder-to-order transitions, 525,532,542−545 whereas mixed mechanisms have been suggested for others. 530,546−548 Given their high degree of conformational plasticity, disordered proteins may be particularly prone to mixed binding behaviors exhibiting features of both induced fit and conformational selection. 522,537,542,543,545,549−556 As pointed out by Hammes et al, solution conditions and protein concentrations additionally affect the mechanistic properties of disorder-to-order transitions.…”

Section: Biological Properties Of Idps Inside Cellsmentioning

confidence: 99%

Physicochemical Properties of Cells and Their Effects on Intrinsically Disordered Proteins (IDPs)

Binolfi²,

et al. 2014

View full text Add to dashboard Cite

“…Additional future directions include an evaluation of the role of inhibitor chemistry in defining binding mode diversity via ensemble simulations of a large and chemically-disparate set of inhibitors, and characterization of the mechanism of protein-ligand association, which has once again become a pronounced point of discussion in the biochemical and biophysical communities [14,36]. …”

Section: Resultsmentioning

confidence: 99%

“…A primary supposition of classical models of protein-ligand binding is that the binding event results in a single, lowest-energy protein-ligand configuration [14], which implicitly assumes that both protein and bound ligand suffer significant penalties in configurational entropy upon binding, thereby requiring an enthalpic counterbalance to overcome this entropy loss. In contrast, we observe a significant number of inhibitor-accessible binding modes that not only endow the inhibitor with unpredicted, residual conformational entropy, but also allow for continued protein flexibility after ligand binding.…”

Section: Introductionmentioning

confidence: 99%

Ensemble Molecular Dynamics of a Protein-Ligand Complex: Residual Inhibitor Entropy Enhances Drug Potency in Butyrylcholinesterase

et al. 2017

View full text Add to dashboard Cite

Butyrylcholinesterase is a key enzyme that catalyzes the hydrolysis of the neurotransmitter acetylcholine and shows an increased activity in patients suffering from Alzheimer’s disease (AD), making this enzyme a primary target in treating AD. Central to this problem, and to similar scenarios involving biomolecular recognition, is our understanding of the nature of the protein-ligand complex. The butyrylcholinesterase enzyme was studied via all-atom, explicit solvent, ensemble molecular dynamics simulations sans inhibitor and in the presence of three dialkyl phenyl phosphate inhibitors of known potency to a cumulative sampling of over 40 μs. Following the relaxation of these ensembles to conformational equilibria, binding modes for each inhibitor were identified. While classical models, which assume significant reduction in protein and ligand conformational entropies, continue to be favored in contemporary studies, our observations contradict those assumptions: bound ligands occupy many conformational states, thereby stabilizing the complex, while also promoting protein flexibility.

show abstract

From “fluctuation fit” to “conformational selection”: Evolution, rediscovery, and integration of a concept

Cited by 33 publications

References 40 publications

Promiscuous and specific recognition among ephrins and Eph receptors

Promiscuous and specific recognition among ephrins and Eph receptors

Physicochemical Properties of Cells and Their Effects on Intrinsically Disordered Proteins (IDPs)

Ensemble Molecular Dynamics of a Protein-Ligand Complex: Residual Inhibitor Entropy Enhances Drug Potency in Butyrylcholinesterase

Contact Info

Product

Resources

About