Structure and aggregation proclivity of C 12 E 3 in aqueous solution Ts. Zahariev, A. Ivanova ⇑ , M. Velinova, A. Tadjer University of Soﬁa, Faculty of Chemistry and Pharmacy, 1 James Bourchier Blvd., 1164 Soﬁa, Bulgaria article info Article history: Received 27 June 2012 In ﬁnal form 16 October 2012 Available online 27 October 2012 Keywords: Dodecyl oligo(ethylene glycols) DFT calculations ONIOM calculations Binding energy Solvent-accessible surface Molecular conformations abstract Olygo(ethylene glycol) alkyl ethers – C x E y are well known for their high surface activity and rich phase behavior. These substances exhibit some unusual aggregation characteristics in aqueous solution even at concentrations well below CMC attributed to the formation of pre-aggregates of small size, e.g., dimers. To verify this, a series of C 12 E 3 dimers with initial geometries taken from coarse-grained molecular dynamics simulations is subject to geometry optimization with two quantum chemical methods: DFT and ONIOM in implicit water solvent. The resulting structures are classiﬁed into groups based on struc- tural parameters. Their stability is assessed by relative and binding energy and rationalized in terms of molecular characteristics. All studied dimers are stable and various mutual alignments of the surfactants therein are feasible. The loss of surface area is outlined as the predominant stabilizing factor. Substantial number of the structures is suitable for further aggregation. Ó 2012 Elsevier B.V. All rights reserved. 1. Introduction Recently, the application of drug-loaded nanosized drug carriers such as liposomes, micelles, polymeric nanoparticles and dendri- mers in systemic chemotherapy has received much attention [1– 3]. Loading of chemotherapeutic agents into nanosized carriers has several advantages compared to the standard drug administra- tion. Stealth nanoparticles increase signiﬁcantly the bioavailability of the drug, since most low-molecular-weight drug molecules are neutralized in the liver and kidneys. Moreover, hydrophobic drugs are administered intravenously after dissolution in ethanol or Cremophor El, which leads to some toxic side effects [4,5]. If drug molecules are incorporated in micelles, the need of bioactive adju- vants is avoided. There are several requirements to all membrane- penetrating nanocarriers that are used in chemotherapy [6]. The nanotransporters should be non-toxic, biocompatible and must have a structure similar to the cell membrane bilayer. Poly(ethylene glycol) alkyl ethers seem relatively suitable com- ponents for such micellar structures. These surfactants have a gen- eral chemical formula H(CH 2 ) x  (OCH 2 CH 2 ) y OH, or simply C x E y , where x is the number of carbon atoms in the hydrocarbon chain and y refers to the number of oxyethylene units. In water these surfactants, especially the long-chained C x E y , are characterized by a complex behavior, which includes formation of micellar and lamellar phases [7–10]. There is experimental evidence that solutions of C x E y exhibit extraordinary behavior at concentrations far below the critical mi- celle concentration (CMC) [11], namely, formation of plateaus in the rheological isotherms, which are indicative of aggregation processes. A hypothesis has been proposed [12] explaining this phenomenon with small pre-aggregates existing even at concen- trations 10 7 –10 6 mol l 1 . The process of self-assembly of C x E y is quite complex and it is inﬂuenced by a variety of factors including intramolecular param- eters (molecular volume, solvent-accessible surface) and thermo- dynamic variables such as temperature or concentration. Therefore, computational modeling aids substantially the determi- nation of the nature and driving forces of the pre-aggregation events at the molecular level. The present study is focused on the C 12 E 3 molecules, which are known to possess the longest water-soluble alkyl chain (C 12 H 25 ) and the shortest olygo(ethylene glycol) chain from all water- soluble C 12 E y molecules. The phase behavior of C 12 E 3 is well studied, noting that this surfactant has a certain afﬁnity to the for- mation of lamellar phases [13]. Its analogues with dodecyl alkane tail and varying length of the hydrophilic head are also frequent objects of experimental studies showing multi-facetted phase behavior [14–16]. Previous theoretical studies of C 12 E y (3 6 y 6 5) include quantitative structure–property relationship (QSPR) models, thermodynamics-based calculations, molecular dynamics (MD) and Monte Carlo (MC) simulations of poly(ethylene glycol) mole- cules in water as well as in different phases (micelles, monolayers at the air/water interface) [7,17–27]. CMC or surface tension of poly(ethylene glycol) alkyl ethers and other surfactants with similar 0301-0104/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.chemphys.2012.10.005 ⇑ Corresponding author. Tel.: +359 28161374; fax: +359 29625438. E-mail addresses: cvetanzah@gmail.com (Ts. Zahariev), aivanova@chem.uni- soﬁa.bg (A. Ivanova), mariq.velinova@gmail.com (M. Velinova), tadjer@chem.uni- soﬁa.bg (A. Tadjer). Chemical Physics 410 (2013) 1–8 Contents lists available at SciVerse ScienceDirect Chemical Physics journal homepage: www.elsevier.com/locate/chemphys