The role of dynamic conformational ensembles in biomolecular recognition

By David D. Boehr, Ruth Nussinov, Peter E. Wright. 2009

1,888 citations recorded by the source corpus.

Molecular recognition is central to all biological processes. For the past fifty years, Koshland’s ‘induced fit’ hypothesis has been the textbook explanation for molecular recognition events. However, recent experimental evidence supports an alternative mechanism. ‘Conformational selection’ postulates that all protein conformations pre-exist, and the ligand selects the most favored conformation. Following binding the ensemble undergoes a population shift, redistributing the conformational states. Both conformational selection and induced fit appear to play roles. Following binding by a primary conformational selection event, optimization of side-chain and backbone interactions is likely to proceed by an induced fit mechanism. Conformational selection has been observed for protein-ligand, protein-protein, protein-DNA, protein-RNA and RNA-ligand interactions. These data support a new molecular recognition paradigm for processes as diverse as signaling, catalysis, gene regulation, and protein aggregation in disease, which has the potential to significantly impact our views and strategies in drug design, biomolecular engineering and molecular evolution.

Subfields: Molecular Biology

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In Molecular Biology

1. Jens Meiler
2. David Baker
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4. Tanja Kortemme
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Citations in the corpus

• Sampling alternative conformational states of transporters and receptors with AlphaFold2 (2022, background): “Dynamic interconversion between multiple conformations underpins the functions of integral membrane proteins in all domains of life ( Campbell et al., 2016 ; Cournia et al., 2015 ; Shaw et al., 2010 ; Boehr et al., 2009 ).”
• AlphaDesign: A de novo protein design framework based on AlphaFold (2021, background): “Secondly, many proteins also undergo conformational changes with a well-described equilibrium between states, making use of these changes to enact function [22].”
• Ligand–receptor interaction platforms and their applications for drug discovery (2012, background): “However, increasing evidence suggests that a target protein is dynamic in solution and in cells and may sample a vast ensemble of conformations; the ligand selects the most favored conformation for binding [13].”
• Insights into Protein–Ligand Interactions: Mechanisms, Models, and Methods (2016, methodology): “This step may not “induce” a conformational change and is similar to the binding process described by the lock-and-key model [59].”
• Stochastic mechano-chemical kinetics of molecular motors: A multidisciplinary enterprise from a physicist’s perspective (2012, background): “The difference between the induced-fit mechanism and the conformation selection mechanism can be elucidated in terms of (i) a dynamic landscape [350, 351, 354, 355] and (ii) kinetic pathways through discrete states [356, 357] (see fig.”
• The s2D method: simultaneous sequence-based prediction of the statistical populations of ordered and disordered regions in proteins. (2015, background): “Proteins folded in their native states experience conformational fluctuations, which in many cases facilitate their functions [1–6].”
• Estimating conformational heterogeneity of tryptophan synthase with a template‐based Alphafold2 approach (2022, background): “…the exploration of additional conformational states presenting properly positioned loops and flexible domains gating the active site access, 11,12 (2) activation of the substrate(s) for productive enzyme-substrate (ES) formation; (3) stabilization of the transition state(s) leading to the…”
• Beyond directed evolution - semi-rational protein engineering and design (2010, background): “Along the same lines, the exclusion of conformational heterogeneity in proteins and conformational changes associated with catalysis in current enzyme designs could also explain the similar catalytic performance of de novo enzymes and their corresponding catalytic antibodies [35,36].”
• Computational Design of Ligand Binding Proteins with High Affinity and Selectivity (2013, background): “…binding sites: (1) specific energetically favourable hydrogen-bonding and van der Waals interactions with the ligand; (2) high overall shape complementarity to the ligand; and (3) structural pre-organization in the unbound protein state, which minimizes entropy loss upon ligand binding 15,16 .”