Allostery: The "Second Secret of Life" & Its Growing Impact on Science - a blogpost by ESR7 Vincenzo Di Lorenzo

Over a century ago, Christian Bohr observed that carbon dioxide affects oxygen binding to hemoglobin—a phenomenon called the Bohr effect, an early glimpse into allostery. Fast forward to 1961, Jacques Monod and François Jacob coined the term “allosteric inhibition,” setting the stage for decades of groundbreaking research.

At its core, allostery describes how a molecule binding at one site of a protein can influence another distant site, namely the active site, enabling regulation at a distance—a fundamental feature of life. This is due to the fact that binding sites are energetically connected/coupled. But how does it work? Scientists developed three key models to explain it:

1. MWC Model (Concerted Model) – The protein switches between two states as a whole. Ligand binding shifts equilibrium toward the active state, like a team moving together.
2. KNF Model (Sequential Model) – Instead of an all-at-once switch, changes happen step by step, propagating structural shifts gradually across the protein, like a domino effect.
3. Ensemble Allostery Model (EAM) – Ensemble Allostery Model (EAM) – A modern and comprehensive model, integrating both MWC and KNF:
   ✅ Proteins exist in multiple conformations at once.
   ✅ Ligand binding reshapes the energy landscape, shifting populations dynamically.
   ✅ Distant sites are affected in a flexible, adaptable manner.

EAM is currently the most realistic, dynamic, and widely accepted view of allostery, revolutionizing our understanding of molecular regulation and drug discovery.

From Experiment to Computation: Cracking the Allosteric Code
For decades, X-ray crystallography provided key snapshots of allosteric proteins. But since allostery is a dynamic process, techniques like NMR spectroscopy, hydrogen-deuterium exchange mass spectrometry (HDXMS), all-atom molecular dynamics simulation and coarse-grained simulations are able to reveal hidden transient states and allosteric networks.
With advances in computational biology, molecular simulations allow us to even predict allosteric sites, simulate population shifts, and design allosteric drugs. The first FDA-approved allosteric drug in 2004 was a milestone—today, allosteric modulation is revolutionizing drug discovery.

At ALLODD, we are actively investigating allostery to push the boundaries of drug discovery. As part of this initiative, 14 PhD students are being trained in allosteric drug discovery, working to unravel allosteric mechanisms and develop novel therapeutic strategies.

The Future of Allostery: Unlocking the "Second Secret of Life"
Monod called allostery "the second secret of life", and its full potential is only just being uncovered. By linking genetic codes with allosteric mechanisms, we may soon crack the allosteric code, offering new ways to tackle diseases like cancer.

Despite decades of research, many questions remain:
🔹 How do entropy and enthalpy drive allostery?
🔹 What role does it play in protein disorder?
🔹 Can allosteric networks be fully mapped in living cells?
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One thing is clear: Allostery is no longer just a biochemical curiosity— it’s rooted in the fundamental physical properties of macromolecular systems and it’s the key to unlocking new biology and next-generation therapies

​Image credits: Raza, S.H.A., Zhong, R., Yu, X. et al. Advances of Predicting Allosteric Mechanisms Through Protein Contact in New Technologies and Their Application. Mol Biotechnol 66, 3385–3397 (2024). https://doi.org/10.1007/s12033-023-00951-4