Most therapeutic agents suffer from poor solubility, rapid clearance from the blood stream, a lack of targeting, and often poor translocation ability across cell membranes. Drug/gene delivery systems (DDSs) are capable of overcoming some of these barriers to enhance delivery of drugs to their right place of action, e.g. inside cancer cells. In this review, we focus on nanoparticles as DDSs. Complementary experimental and computational studies have enhanced our understanding of the mechanism of action of nanocarriers and their underlying interactions with drugs, biomembranes and other biological molecules. We review key biophysical aspects of DDSs and discuss how computer modeling can assist in rational design of DDSs with improved and optimized properties. We summarize commonly used experimental techniques for the study of DDSs. Then we review computational studies for several major categories of nanocarriers, including dendrimers and dendrons, polymer-, peptide-, nucleic acid-, lipid-, and carbon-based DDSs, and gold nanoparticles. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.

The distribution of ionizable amino lipids (KC2) is critical in structure of lipid nanoparticles, siRNA entrapment and endosomal release. Neutral KC2 segregates from phospholipids (POPC) and forms an oily core in the bilayer interior.

The activity of CTP:phosphocholine cytidylyltransferase (CCT), a key enzyme in phosphatidylcholine synthesis, is regulated by reversible interactions of a lipid-inducible amphipathic helix (domain M) with membrane phospholipids. When dissociated from membranes, a portion of the M domain functions as an auto-inhibitory (AI) element to suppress catalysis. The AI helix from each subunit binds to a pair of α helices (αE) that extend from the base of the catalytic dimer to create a four-helix bundle. The bound AI helices make intimate contact with loop L2, housing a key catalytic residue, Lys The impacts of the AI helix on active-site dynamics and positioning of Lys are unknown. Extensive MD simulations with and without the AI helix revealed that backbone carbonyl oxygens at the point of contact between the AI helix and loop L2 can entrap the Lys side chain, effectively competing with the substrate, CTP. , removal of the AI helices dramatically increased αE dynamics at a predicted break in the middle of these helices, enabling them to splay apart and forge new contacts with loop L2. cross-linking confirmed the reorganization of the αE element upon membrane binding of the AI helix. Moreover, when αE bending was prevented by disulfide engineering, CCT activation by membrane binding was thwarted. These findings suggest a novel two-part auto-inhibitory mechanism for CCT involving capture of Lys and restraint of the pliable αE helices. We propose that membrane binding enables bending of the αE helices, bringing the active site closer to the membrane surface.

Inverted/reverse hexagonal (H II ) phases are of special interest in several fields of research, including nanomedicine. We used molecular dynamics (MD) simulation to study H II systems composed of dioleoylphosphatidylethanolamine (DOPE) and palmitoyloleoylphosphatidylethanolamine (POPE) at several hydration levels and temperatures. The effect of the hydration level on several H II structural parameters, including deuterium order parameters, was investigated. We further used MD simulations to estimate the maximum hydrations of DOPE and POPE H II lattices at several given temperatures. Finally, the effect of acyl chain unsaturation degree on the H II structure was studied via comparing the DOPE with POPE H II systems. In addition to MD simulations, we used deuterium nuclear magnetic resonance ( 2 H NMR) and small-angle X-ray scattering (SAXS) experiments to measure the DOPE acyl chain order parameters, lattice plane distances, and the water core radius in H II phase DOPE samples at several temperatures in the presence of excess water. Structural parameters calculated from MD simulations are in excellent agreement with the experimental data. Dehydration decreases the radius of the water core. An increase in hydration level slightly increased the deuterium order parameter of lipids acyl chains, whereas an increase in temperature decreased it. Lipid cylinders undulated along the cylinder axis as a function of hydration level. The maximum hydration levels of PE H II phases at different temperatures were successfully predicted by MD simulations based on a single experimental measurement for the lattice plane distance in the presence of excess water. An increase in temperature decreases the maximum hydration and consequently the radius of the water core and lattice plane distances. Finally, DOPE formed H II structures with a higher curvature compared to POPE, as expected. We propose a general protocol for constructing computational H II systems that correspond to the experimental systems. This protocol could be used to study H II systems composed of molecules other than the PE systems used here and to improve and validate force field parameters by using the target data in the H II phase.