Generating Multistate Conformations of P-type ATPases with a Conditional Diffusion Model

Understanding and predicting the diverse conformational states of membrane proteins is essential for elucidating their biological functions. Despite advancements in computational methods, accurately capturing these complex structural changes remains a significant challenge. Here, we introduce a computational approach to generate diverse and biologically relevant conformations of membrane proteins using a conditional diffusion model. Our approach integrates forward and backward diffusion processes, incorporating state classifiers and additional conditioners to control the generation gradient of conformational states. We specifically targeted the P-type ATPases, a critical family of membrane transporters, and constructed a comprehensive data set through a combination of experimental structures and molecular dynamics simulations. Our model, incorporating a graph neural network with specialized membrane constraints, demonstrates exceptional accuracy in generating a wide range of P-type ATPase conformations associated with different functional states. This approach represents a meaningful step forward in the computational generation of membrane protein conformations using AI and holds promise for studying the dynamics of other membrane proteins.