Breakthrough transforms protein simulations
Introduction
Biomedical Engineering Associate Professor Ao Ma and postdoctoral associate Huiyu Li achieved a breakthrough in computational biophysics by introducing a novel computational method that enables efficient predictive sampling of functionally important large-scale protein conformational changes, which solved a decades-long challenge.
The paper, “Enhanced sampling of protein conformational changes via true reaction coordinates from energy relaxation,” was published this winter and unveils a game-changing approach to simulating how proteins transition between different structures—an essential process in biological function, with groundbreaking implications for drug design and enzyme engineering.
Simulations are computational models that help scientists understand and design biological molecules and their interactions. These simulations aim to mimic what happens in nature, however, there are significant limitations.
“Identifying the exact reaction coordinates has been the central challenge in the field since the early 2000s,” Ma said. Traditional molecular dynamics simulations cannot typically capture protein conformational change, spanning milliseconds to hours.
Ma and Li’s novel approach overcomes these fundamental limitations by directly computing these true reaction coordinates from a very fast process called energy relaxation, which only lasts a few picoseconds. relaxation is when a small amount of excess energy is injected into the active side of a protein, triggering systemic motion to dissipate into the environment before the protein energy returns to its equilibrium value.
Understanding protein conformational changes is critical for designing next-generation therapeutics.
“If we understand the ligand binding process, we can design better drugs that can outcompete natural ligands, making them more selective and reducing unintended side effects,” Ma said.