Atlasing of Assembly Landscapes using Distance Geometry and Graph Rigidity.

Abstract

This Article describes a novel geometric methodology for analyzing free energy and kinetics of assembly driven by short-range pair-potentials in an implicit solvent and provides a proof-of-concept illustration of its unique capabilities. An atlas is a labeled partition of the assembly landscape into a roadmap of maximal, contiguous, nearly-equipotential-energy conformational regions or macrostates, together with their neighborhood relationships. The new methodology decouples the roadmap generation from sampling and produces: (1) a queryable atlas of local potential energy minima, their basin structure, energy barriers, and neighboring basins; (2) paths between a specified pair of basins, each path being a sequence of conformational regions or macrostates below a desired energy threshold; and (3) approximations of relative path lengths, basin volumes (configurational entropy), and path probabilities. Results demonstrating the core algorithm's capabilities and high computational efficiency have been generated by a resource-light, curated open source software implementation EASAL (Efficient Atlasing and Search of Assembly Landscapes, ACM Trans. Math. Softw. 2018 44, 1-48. 10.1145/3204472; see software, Efficient Atlasing and Search of Assembly Landscapes, 2016. https://bitbucket.org/geoplexity/easal; video, Video Illustrating the opensource software EASAL, 2016. https://cise.ufl.edu/~sitharam/EASALvideo.mpeg; and user guide, EASAL software user guide, 2016. https://bitbucket.org/geoplexity/easal/src/master/CompleteUserGuide.pdf). Running on a laptop with Intel(R) Core(TM) i7-7700@3.60 GHz CPU with 16GB of RAM, EASAL atlases several hundred thousand conformational regions or macrostates in minutes using a single compute core. Subsequent path and basin computations each take seconds. A parallelized EASAL version running on the same laptop with 4 cores gives a 3× speedup for atlas generation. The core algorithm's correctness, time complexity, and efficiency-accuracy trade-offs are formally guaranteed using modern distance geometry, geometric constraint systems and combinatorial rigidity. The methodology further links the shape of the input assembling units to a type of intuitive and queryable bar-code of the output atlas, which in turn determine stable assembled structures and kinetics. This succinct input-output relationship facilitates reverse analysis and control toward design. A novel feature that is crucial to both the high sampling efficiency and decoupling of roadmap generation from sampling is a recently developed theory of convex Cayley (distance-based) custom parametrizations specific to assembly, as opposed to folding. Representing microstates with macrostate-specific Cayley parameters, to generate microstate samples, avoids gradient-descent search used by all prevailing methods. Further, these parametrizations convexify conformational regions or macrostates. This ratchets up sampling efficiency, significantly reducing number of repeated and discarded samples. These features of the new stand-alone methodology can also be used to complement the strengths of prevailing methodologies including Molecular Dynamics, Monte Carlo, and Fast Fourier Transform based methods.