The function of biomolecules such as proteins depends on their ability to interconvert between a wide range of structures or "conformations." Researchers have endeavored for decades to develop computational methods to predict the distribution of conformations, which is far harder to determine experimentally than a static folded structure. We present ConforMix, an inference-time algorithm that enhances sampling of conformational distributions using a combination of classifier guidance, filtering, and free energy estimation. Our approach upgrades diffusion models -- whether trained for static structure prediction or conformational generation -- to enable more efficient discovery of conformational variability without requiring prior knowledge of major degrees of freedom. ConforMix is orthogonal to improvements in model pretraining and would benefit even a hypothetical model that perfectly reproduced the Boltzmann distribution. Remarkably, when applied to a diffusion model trained for static structure prediction, ConforMix captures structural changes including domain motion, cryptic pocket flexibility, and transporter cycling, while avoiding unphysical states. Case studies of biologically critical proteins demonstrate the scalability, accuracy, and utility of this method.
ZeroFold: Protein-RNA Binding Affinity Predictions from Pre-Structural Embeddings
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge（错误折叠疾病中心，尤斯夫·哈米埃德化学系，剑桥大学）；Medicinal Chemistry, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca（药物化学，研发与早期开发，呼吸与免疫学，生物制药研发，阿斯利康）
Fold'EM: Direct atomic structure inference from Cryo-EM particles
Institute of Science and Technology Austria（奥地利科学技术研究所）；University of Zurich（苏黎世大学）；Frankfurt Institute for Advanced Studies（法兰克福高等研究院）；Princeton University（普林斯顿大学）；Broad Institute of MIT and Harvard（麻省理工学院和哈佛大学博德研究所）
ProtTeX: Structure-In-Context Reasoning and Editing of Proteins with Large Language Models
Changping Laboratory（昌平实验室）；School of Computer Science and Technology, Soochow University（苏州大学计算机科学与技术学院）；College of Chemistry and Molecular Engineering, Peking University（北京大学化学与分子工程学院）
