Integrative multiscale modeling of transport through the nuclear pore complex

Living cells, tissues, and entire organisms can all be modeled as
dynamic systems of moving parts. The interactions between these
parts give rise to the collective behavior of these systems, which
ultimately yields Life. Experimental or theoretical methods for
characterizing biological systems are typically restricted to only
subsets of relevant spatial and temporal scales, limiting their
utility for characterizing these systems holistically. Integrative
multiscale modeling is a general approach for bridging this gap by
systematically combining data from different methods at different
scales. Using this approach, we modeled the nucleocytoplasmic
transport system, which regulates the molecular traffic in and out of
the cell’s nucleus. This system comprises many millions of atoms that
interact over a wide range of timescales and plays a key role in both
health and disease. We modeled the entire transport system based on
data from a large number of experimental and theoretical sources,
specified at multiple scales and varying degrees of data
uncertainties. The resulting spatiotemporal model recapitulates
independent experimental measurements of transport rates and
elucidates fundamental properties of the transport system, including
the mechanism by which it filters by size and how it functions both
rapidly and selectively at the same time. As we now strive to expand
the scope and depth of our modeling, I will also discuss our ongoing
efforts to develop new and more efficient algorithms for integrative
modeling of dynamic biological systems in high-dimensional
configuration spaces, by efficiently propagating local computations in
a hierarchy of spatial and temporal scales of representation.