#31 · Structural bio & protein design

Simulations probe DNA junction metastability, KRAS dynamics and least-action protein…

The dominant thread is the use of physics-based sampling and free-energy estimation to quantify the energetics and populations of biomolecular states. Atomistic molecular dynamics with REUS free-energy calculations places parallel DNA Holliday junctions in a metastable local minimum populated below 1%. Alchemical thermodynamic cycles combined with A-EDS fragment screening supply relative binding free energies for KRAS and inform the relationship between affinity and conformational dynamics. A least-action mechanistic model, validated on beta-lactamase, takes a different route, using stability and epistasis to identify probable evolutionary pathways rather than sampling trajectories directly. What is new across the set is the extension of these energetic frameworks beyond static structure toward evolutionary trajectories and state populations. The evidence is preprint-heavy, and the evolutionary model is tested on a single protein.