Edited by Alex TokerSpatial and temporal control of actin polymerization is fundamental for many cellular processes, including cell migration, division, vesicle trafficking, and response to agonists. Many actin-regulatory proteins interact with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) and are either activated or inactivated by local PI(4,5)P 2 concentrations that form transiently at the cytoplasmic face of cell membranes. The molecular mechanisms of these interactions and how the dozens of PI(4,5)P 2sensitive actin-binding proteins are selectively recruited to membrane PI(4,5)P 2 pools remains undefined. Using a combination of biochemical, imaging, and cell biologic studies, combined with molecular dynamics and analytical theory, we test the hypothesis that the lateral distribution of PI(4,5)P 2 within lipid membranes and native plasma membranes alters the capacity of PI(4,5)P 2 to nucleate actin assembly in brain and neutrophil extracts and show that activities of formins and the Arp2/3 complex respond to PI(4,5)P 2 lateral distribution. Simulations and analytical theory show that cholesterol promotes the cooperative interaction of formins with multiple PI(4,5)P 2 headgroups in the membrane to initiate actin nucleation. Masking PI(4,5)P 2 with neomycin or disrupting PI(4,5)P 2 domains in the plasma membrane by removing cholesterol decreases the ability of these membranes to nucleate actin assembly in cytoplasmic extracts.

The morphologies of cell membranes, and specifically the local curvature distributions are determined either by its intrinsic components such as lipids and membrane-associated proteins or by the adhesion forces due to membrane interactions with the cytoskeleton, extracellular matrix (ECM) and other cells in the tissue, as well as physical variables such as membrane and frame tensions. We present a computational analysis for a model of pinned membranes based on the dynamically triangulated Monte Carlo (MC) model for membranes. We show that membrane adhesion to ECM or a substrate promotes curvature generation on cell membranes, and this process depends on the excess area, or equivalently membrane tension, and the density of adhesion sites. This biophysics based model predicts adhesion induced biogenesis of microvesicles in cell membranes. For a moderate density of adhesion sites and high excess membrane area, an increase in membrane tension can result in the formation of microvesicles and tubules on the membrane. We also demonstrate the significance of intrinsically curved proteins in promoting vesiculation on pinned membranes. The results presented here are relevant to the understanding of microvesicle biogenesis and curved membrane topographies due to physical factors such as substrate stiffness and ECM interactions.

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 timedependent 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)

The dynamics and organization of the actin cytoskeleton are crucial to many cellular events such as motility, polarization, cell shaping, and cell division.