Molecular Dynamics Study of Tryptophylglycine: A Dipeptide Nanotube with Confined Water Yuansheng Pan,* ,† Henrik Birkedal, †,‡ Philip Pattison, †,§ David Brown, || and Gervais Chapuis † Laboratoire de Cristallographie, Ecole Polytechnique Fe ´ de ´ rale de Lausanne, BSP, 1015 Lausanne, Switzerland, Swiss-Norwegian Beam Line, SNBL/ESRF, P.O. Box 220, F-38043 Grenoble, France, and Laboratoire des Mate ´ riaux Organiques a ` Proprie ´ te ´ s Spe ´ cifiques, UMR CNRS 5041, UniVersite ´ de SaVoie, 73376 Le Bourget du Lac, France ReceiVed: October 24, 2003; In Final Form: March 2, 2004 To investigate the mechanism of structural changes of a peptide nanotube and water confined inside the channel, the helical peptide tryptophylglycine monohydrate (WG‚H 2 O) was studied by molecular dynamics (MD) simulations using the three-dimension parallel MD program ddgmq (software package) and a consistent force field. Simulations were performed on both the water-containing system and a model system without water molecules. The details of the structural behavior with temperature are investigated for the entire simulated temperature range. Phase transitions were obtained at 115, 245, 270, 310, and 385 K, due to the contributions of both the peptide and the confined water subsystems. The crystalline, amorphous, liquidlike, liquid, and superheated phases of water were observed in the temperature ranges 40-115, 115-245, 245-310, 310- 385, and >385 K, respectively. At 300 K, the diffusion constant of the confined water is 0.46 × 10 -5 cm 2 s -1 , a value comparable to that of other peptide nanotubes. The empty peptide system melts at 440 K. Mechanisms of the negative thermal expansion (NTE) along the tube axis were investigated for different temperature ranges. The contraction of the crystalline water (or amorphous water) draws also the tube walls in and leads to NTE below 245 K. The other NTEs appear to be connected to the collapse of the ice network or the solid peptide network between 245 K and room temperature or from 310 to 440 K, respectively. 1. Introduction Following the discoveries of self-assembling peptide sys- tems, 1,2 synthetic and natural supramolecular tubular assemblies have become of great interest owing to their potential use as cross-membrane conduits, 3,4 as membrane piercing antibacteri- als, 5 and, in the case of synthetic systems, as model systems for natural tubular systems such as porins and ion-channel proteins. 4,6 In 1993, Ghadiri and co-workers 1 demonstrated that nanotubes can be self-assembled by a process based on -sheetlike interactions between macrocyclic D,L-peptides. Subsequent work by Ghadiri and several others 4,7-11 revealed other examples of polypeptide architecture that could lead to nanotube formation through vertical stacking of cyclic peptides. In the chemical literature, these peptidic systems have received significant interest because of their properties, but the alternative use of carbon nanotubes 12 has also been the focus of strong efforts. It was recently found by Go ¨rbitz that certain linear L,L- dipeptides also form peptide nanotubes. 9 In L-Leu-L-Leu (LL), L-Leu-L-Phe (LF), and L-Phe-L-Leu (FL), four dipeptide mol- ecules form the outskirt of a hydrophilic region, which contains water molecules in the core channel. The four dipeptide molecules display a pseudotetragonal symmetry, with a water- filled channel of 10 Å diameter. In a similar way, the crystal structure of six dipeptide molecules of L-Phe-L-Phe (FF) create a somewhat larger channel. Tryptophylglycine monohydrate (WG‚H 2 O, Figure 1) 10,11 is another example of a dipeptide that forms an extended, one- dimensional, water-filled tubular structure. This system displays several unusual features, one in particular being uniaxial negative thermal expansion along the tube axis. 11 Here, the symmetry is truly tetragonal, with space group symmetry P4 1 . The tube axis is parallel to the tetragonal c-axis. Compared to the rather confined volumes in the channels of LL and LF with dimensions of 2.5 × 6.0 Å and FL with 4.0 × 6.0 Å, the internal cross section of the WG nanotube, 8.3 × 8.3 Å, is relatively large. WG is a dipeptide expressed in the human hypophysis. The activity of this compound is not yet known. It was located as a fluorescent hypophyseal extract from adult human brains. 13 Vellucci and Webster found a sedative effect in mice, evidenced by a decreased locomotor and exploratory activity. 14 They further found that WG also reduces rectal temperature, decreases the convulsive action of the drug leptazol, and increases the antileptazol effect of diazepam in mice. * Corresponding author. Telephone: +41-21-693 0638. Fax: +41-21- 693 0504. E-mail: Yuansheng.Pan@epfl.ch. † Ecole Polytechnique Fe ´de ´rale de Lausanne. ‡ Present address: Department of Chemistry, University of Aarhus, Langelandsgade 140, DK-8000 Aarhus C, Denmark. § Swiss-Norwegian Beam Line. || Universite ´ de Savoie. Figure 1. Tryptophylglycine. 6458 J. Phys. Chem. B 2004, 108, 6458-6466 10.1021/jp037219v CCC: $27.50 © 2004 American Chemical Society Published on Web 04/28/2004