Mechanical principle of allostery
A research team at the Max Planck Institute (MPI) for Multidisciplinary Sciences has discovered a previously unknown mechanism that allows mechanical signals to travel across proteins. The lever-like principle makes allostery physically tangible and opens new perspectives for drug design and synthetic biology.
The “allosteric lever” mechanism explains how structural changes are transmitted specifically across proteins over large distances.
The scientists showed that in proteins with allosteric activity, localized, stiff motions are specifically coupled to softer large-scale deformations, whereas such specific coupling is absent at non-allosteric sites.
The new insight may be useful for designing new biomolecules with modulated allosteric properties, as well as for drug design and synthetic biology.
Allostery is the process by which a distortion at one site of a molecule, for instance the binding of a ligand, affects the activity at a distant site. This process enables the control over the function of proteins and nucleic acids. Take for example hemoglobin, the oxygen-carrying protein in blood: When one oxygen molecule binds to it, the entire protein changes shape, making it easier for additional oxygen molecules to bind.
Explaining allostery
Despite its central role in biology, the physical basis of allostery has remained elusive. It cannot be fully explained by typical structural motifs, characteristic dynamic behaviors, or simple thermodynamic principles. Instead, it appears to require complex, coordinated motions that depend intricately on the molecular structure. Maximilian Vossel, Bert de Groot, and Aljaz Godec at the MPI for Multidisciplinary Sciences have now identified a specific mechanism which they coin the “allosteric lever”, that explains how structural changes are transmitted across proteins over large distances.
How motion is transmitted
The scientists investigated this mechanism using elastic network models of proteins – simplified representations in which proteins are modeled as networks of springs connecting their amino acids – and developed a method to analyze how the protein structures respond nonlinearly to generic mechanical perturbations such as the binding of a ligand molecule. They discovered that in proteins with allosteric activity, perturbations at key sites induce a specific coupling: Stiff, localized motions are mechanically linked to broader, softer deformations elsewhere in the structure. In contrast, perturbations at non-allosteric sites lead to more uniform and less directed mechanical responses. This coupling mechanism explains how minimal changes in one part of a protein give rise to specific functional effects at remote locations. Interestingly, the amino acid sequences responsible for transmitting these changes tend to be evolutionarily conserved – they occur in many organisms in virtually unchanged form.
Nonequilibrium
The findings confirm the hypothesis that allostery is an inherent property of protein structures that is selectively amplified in certain cases. This response is nonlinear and directional, and only occurs when the molecule is actively perturbed, for example, by the binding of another molecule. This renders allostery a fundamentally nonequilibrium phenomenon – a dynamic process that cannot be understood in terms of equilibrium alone. The new insight may be useful for designing new biomolecules with modulated allosteric properties, as well as for drug design and synthetic biology. (ag/jp)
