conformationselected

Conformationselected refers to a biological and chemical principle in which a ligand, protein, or other molecule interacts with a target by recognizing and stabilizing one of several pre‑existing conformations within a dynamic ensemble. Unlike the induced‑fit model, where binding triggers a structural change, conformationselected implies that the target adopts multiple shapes spontaneously, and the binding partner selects the shape that is already present.

In proteins, thermal motions generate a population of slightly different structures. A small molecule may have a higher affinity for a particular arrangement of secondary elements or side‑chain orientations. Upon binding, the equilibrium shifts toward that conformation, increasing its relative abundance. This mechanism plays a crucial role in substrate specificity and enzyme catalysis, where enzymes often cycle through multiple conformations during the catalytic cycle.

The concept is central to modern drug discovery, particularly for proteins that exhibit high flexibility such as kinases, G‑protein‑coupled receptors, and ion channels. Conformation‑selective inhibitors are designed to bind only to the active form of a kinase, for example, thereby improving specificity and reducing off‑target effects. Structural methods such as X‑ray crystallography, cryo‑electron microscopy, and nuclear magnetic resonance spectroscopy routinely reveal ensembles that support the conformationselected hypothesis.

In immunology, T‑cell receptors undergo a form of conformation selection when they recognize peptide‑MHC complexes. The TCR is pre‑organized into multiple low‑affinity states; binding to the peptide stabilizes the high‑affinity state, initiating signaling.

Conformationselected is often used in computational studies that evaluate the free‑energy landscapes of proteins. Molecular dynamics simulations generate conformational ensembles, and virtual screening campaigns target the most accessible or druggable conformations.

Although the principle was first articulated in the 1960s by S. J. Plath and later expanded by Charles K. W. Hawkins in the context of enzyme dynamics, it has become a foundational concept across structural biology, medicinal chemistry, and immunology.