Modeling the Hydrophobicity of Nanoparticles and Their Interaction with Lipids and Proteins Ali Ramazani, † Taraknath Mandal, † and Ronald G. Larson* Department of Chemical Engineering, University of Michigan, 2300 Hayward Street, Ann Arbor, Michigan, United States * S Supporting Information ABSTRACT: We present a method of modeling nanoparticle (NP) hydrophobicity using coarse-grained molecular dynamics (CG MD) simulations, and apply this to the interaction of lipids with nanoparticles. To model at a coarse-grained level the wettability or hydrophobicity of a given material, we choose the MARTINI coarse-grained force field, and determine through simulation the contact angles of MARTINI water droplets residing on flat regular surfaces composed of various MARTINI bead types (C1, C2, etc.). Each surface is composed of a single bead type in each of three crystallographic symmetries (FCC, BCC, and HCP). While this method lumps together several atoms (for example, one cerium and two oxygens of CeO 2 ) into a single CG bead, we can still capture the overall hydrophobicity of the actual material by choosing the MARTINI bead type that gives the best fit of the contact angle to that of the actual material, as determined by either experimental or all-atom simulations. For different MARTINI bead types, the macroscopic contact angle is obtained by extrapolating the microscopic contact angles of droplets of eight different sizes (containing N w = 3224-22978 water molecules) to infinite droplet size. For each droplet, the contact angle was computed from a best fit of a circular curve to the droplet interface extrapolated to the first layer of the surface. We then examine how small nanoparticles of differing wettability interact with MARTINI dipalmitoylphosphotidylcholine (DPPC) lipids and SP-C peptides (a component of lung surfactant). The DPPC shows a transition from tails coating the nanoparticle to a hemimicelle coating the water-wet NP, as the contact angle of a water droplet on the surface is lowered below ∼60°. The results are relevant to developing a taxonomy describing the potential nanotoxicity of nanoparticle interactions with components in the lung. ■ INTRODUCTION Inorganic nanoparticles (NPs) play an important role in modern nanotechnology because of their applications in electronics, 1-4 optics, 5-9 and medicine 10-14 to name but a few. In particular, their potential applications in biomedical science, including bioimaging, 15-17 biosensing, 18-20 and drug delivery, 21-23 have drawn significant research interest. Recently, both the atomistic 24,25 and coarse-grained 26,27 molecular simulations have been performed extensively to investigate the role of morphology 26 (size and shape) and surface chemistry 28 of an NP in its interaction with membrane and lipids and proteins. Ramalho et al., 27 for example, used coarse- grained simulations to investigate the effect of an NP on the structure and phase transformations of DPPC bilayers. Nangia et al. 29 studied the role of the shape of a NP on its translocation through cell membrane. Hu et al. 30 employed coarse-grained simulations combined with experiments to show how the physiochemical properties of NPs regulate translocation across the pulmonary surfactant monolayer. Simonelli et al., 31 using computer simulations, described how monolayer-protected anionic NPs translocate into cell membranes step by step. Thus, simulation studies can predict the efficiency of a given NP as a diagnostic and therapeutic agent and also help in rational designing of a better NP agent. However, the complexity of structures of even model biosystems limits fully atomistic simulations to relatively short time and length scales. Hence, most of the above-mentioned simulation studies employed a coarse-grained model, often the MARTINI 32 coarse-grained force field, to reduce the numbers of degrees of freedom and to access longer time scales. In the MARTINI model, coarse-grained beads are categorized into polar (P), intermediate polar (N), and apolar (C), among other bead types, depending on their interaction strengths with the water beads. The polarity of a material determines its wettability, which is an important parameter for designing an efficient drug carrier. Apart from the biomedical applications, the MARTINI force field also has been used widely to model surfactants, 32,33 polymers, 34,35 biopolymers, 36,37 and inorganic materials. 38,39 Therefore, it is important to establish the wettability of a material made of the individual MARTINI beads. One important application of such a coarse-grained Received: May 23, 2016 Revised: November 6, 2016 Published: November 16, 2016 Article pubs.acs.org/Langmuir © 2016 American Chemical Society 13084 DOI: 10.1021/acs.langmuir.6b01963 Langmuir 2016, 32, 13084-13094