#5 · Structural bio & protein design

MD ensembles and replica-exchange sampling map folding and binding pathways

The common thread is treating molecular recognition and folding as sampled ensembles, pathways, and landscapes rather than single endpoint structures. Markov-model and VAE pathway clustering of MD simulations maps de novo folding of 20 lasso peptides onto uphill landscapes with entropy-driven steps, while two-dimensional replica-exchange MD (gREST/REUS) resolves encounter regions and intermediates between Abltide's initial approach and its bound pose on Abl kinase. What is new is the emphasis on intermediate-rich landscapes over endpoints. Other items apply related tools with different emphases: MD with alchemical free energy calculations for ochratoxin A aptamer selectivity, RFdiffusion auxiliary potentials for nucleic acid binders, and an AlphaFold3-MD framework that redesigns a fragile α-helical domain into a four-helix bundle.