Post-translational modifications (PTMs) alter the proteome in response to intra- and extracellular signals, providing fundamental information processing in development, homeostasis and disease. Here, ...

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Enhanced sampling simulations require collective variables that effectively accelerate dynamics. Here the authors show how to identify true reaction coordinates from energy relaxation simulations usin...

🌟 🧪 ** 𝗕𝘂𝗳𝗳𝗲𝗿 𝗖𝗵𝗼𝗶𝗰𝗲 𝗦𝗵𝗮𝗽𝗲𝘀 𝗡𝗮𝘁𝗶𝘃𝗲 𝗠𝗦 𝗜𝗻𝘀𝗶𝗴𝗵𝘁𝘀, 𝗪𝗵𝘆 𝗖𝗵𝗼𝗼𝘀𝗶𝗻𝗴 𝗧𝗵𝗲 𝗥𝗶𝗴𝗵𝘁 𝗕𝘂𝗳𝗳𝗲𝗿 𝗠𝗮𝘁𝘁𝗲𝗿𝘀 ** 🧪 🌟 🛎 Overvew: Native mass spectrometry has become a powerful tool for probing protein function, dynamics, and...

The bottleneck in enhanced sampling lies in finding collective variables that effectively accelerate protein conformational changes; true reaction coordinates that accurately predict the committor are the well-recognized optimal choice. However, identifying them requires unbiased natural reactive trajectories, which, paradoxically, require effective enhanced sampling. Using the generalized work functional method, we uncover that true reaction coordinates control both conformational changes and energy relaxation, enabling us to compute them from energy relaxation simulations. Biasing true reaction coordinates accelerates conformational changes and ligand dissociation in PDZ2 domain and HIV-1 protease by 105 to 1015-fold. The resulting trajectories follow natural transition pathways, enabling efficient generation of unbiased reactive trajectories. In contrast, biased trajectories from empirical collective variables display non-physical features. Furthermore, our method uses a single prot