Membrane signalosome: where biophysics meets systems biology.

We opine on the recent advances in experiments and modeling of modular signaling complexes assembled on mammalian cell membranes (membrane signalosomes) in the context of several applications including intracellular trafficking, cell migration, and immune response. Characterizing the individual components of the membrane assemblies at the nanoscale, ranging from protein-lipid and protein-protein interactions, to membrane morphology, and the energetics of emergent assemblies at the subcellular to cellular scales pose significant challenges. Overcoming these challenges through the iterative coupling of multiscale modeling and experiment can be transformative in terms of addressing the gaps between structural biology and super-resolution microscopy, as it holds the key to the discovery of fundamental mechanisms behind the emergence of function in the membrane signalosome.

Multiscale modeling of protein membrane interactions for nanoparticle targeting in drug delivery.

Nanoparticle (NP)-based imaging and drug delivery systems for systemic (e.g. intravenous) therapeutic and diagnostic applications are inherently a complex integration of biology and engineering. A broad range of length and time scales are essential to hydrodynamic and microscopic molecular interactions mediating NP (drug nanocarriers, imaging agents) motion in blood flow, cell binding/uptake, and tissue accumulation. A computational model of time-dependent tissue delivery, providing in silico prediction of organ-specific accumulation of NPs, can be leveraged in NP design and clinical applications. In this article, we provide the current state-of-the-art and future outlook for the development of predictive models for NP transport, targeting, and distribution through the integration of new computational schemes rooted in statistical mechanics and transport. The resulting multiscale model will comprehensively incorporate: (i) hydrodynamic interactions in the vascular scales relevant to NP margination; (ii) physical and mechanical forces defining cellular and tissue architecture and epitope accessibility mediating NP adhesion; and (iii) subcellular and paracellular interactions including molecular-level targeting impacting NP uptake.