Methods category listing 1 | Beckstein Lab

Transition pathways in high dimensional spaces, such as the ones produced by advanced algorithms to sample large conformational changes in macromolecules, are difficult to analyze quantitatively. We introduce a method named Path Similarity Analysis (PSA) that enables us to quantify the similarity between two arbitrary paths and extract the atomic-scale determinants responsible for their differences. PSA is implemented in the MDAnalysis library.

The enzyme adenylate kinase (AdK) undergoes a large hinge-like motion. In 2009, we studied the conformational transition between open and closed E. coli AdK without substrate, i.e. “apo AdK”, with a variety of computational methods. As part of the study we also produced a free energy landscape (a potential of mean force or PMF) as a function of the two domain angles. Here we make the data of the underlying free energy landscape available to other researchers so that they can use them in their own research.

While equilibrium MD is considered the most robust approach to simulating macromolecular conformational changes, conformational transitions are rare events that take place on much faster timescales than the waiting times spent in metastable equilibrium states. Equilibrium simulations thus spend relatively little time sampling actual transition events. Fast transition path sampling methods seek to mitigate the rare event sampling problem, though the full extent to which biased or coarse-grained approaches can replicate physical ensembles of transitions is unknown.