The committor is the optimal reaction coordinate for a rare transition: it pinpoints the transition state and fixes the rate, and it governs events from protein folding to crystal nucleation. It minimises a Dirichlet energy, whose value at the minimum is the reactive flux, over functions that vanish on the reactant state and equal one on the product state. In high dimensions such a trial space is very hard to build. Here we rewrite the variational principle so that the boundary conditions are replaced by a normalisation of one boundary observable, the fidelity. Any trial function is then admissible, including functions that cannot satisfy the boundary values at all. On this basis we estimate the high-dimensional committor and rates from one-dimensional profiles along projected coordinates, taking as input only pre-existing equilibrium or reweighted configurations, a diffusion constant estimate, and the two state definitions. The optimum has a closed form that is cheap to evaluate. We obtain committors for AIB9 and villin HP-35 in full torsion space, and folding and unfolding rates for chignolin from umbrella sampling alone.
M. Petersen, Simon M. Lichtinger, Roberto Covino· 0 citations
Physics-based models of biomolecular systems that explicitly represent biomolecular structure and mechanics, such as atomistic molecular dynamics simulations are well-established because experimental data has been available to iteratively improve and validate models. Now, simulations of the biological mesoscale are growing in importance because of the improvements in experimental tools to visualise this regime. This includes techniques such as cryo-electron microscopy and tomography, microscopies that follow individual proteins in their cellular contexts, in situ scattering to follow the dynamic evolution of biomolecular assembly, and -omics tools. Together, these approaches alone and in combination have revealed the importance of interactomes that bridge multiple scales. Here we describe the theoretical, computational and cultural challenges that need to be overcome to gain an understanding of the biological mesoscale and offer potential solutions. This commentary is the result of a joint CECAM/CCPBioSim discussion workshop on how the community should address the challenges of biomolecular simulations at the mesoscale held in Trento, Italy in the summer of 2024. The aim is to provide a broad overview of the tools and techniques relevant to the biological mesoscale, and to signpost the reader to more detailed discussions within the cited literature.
Sarah Harris, Gianluca Lattanzi, Angelo Rosa et al.· Biophysical Journal· 0 citations
This work proposes a method to compute accurate kinetics for general ligand-unbinding problems at modest computational expense and minimal fine tuning, building on the AIMMD path sampling framework and opting for modelling the committor with a single descriptor-free, equivariant graph neural network shared across all systems.
Simon M. Lichtinger, Roberto Covino· 0 citations
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