Molecular dynamics simulation of human immunodeficiency virus protein U (Vpu) in lipid/water Langmuir monolayer

Virus protein U (Vpu) is an accessory membrane protein encoded by human immunodeficiency virus type 1 (HIV-1). Various NMR and CD studies have shown that the transmembrane domain of Vpu has a helical conformation and that the cytoplasmic domain adopts the helix-loop-helix-turn motif. This 3.5-ns molecular dynamics (MD) simulation of Vpu in a lipid/membrane environment has fully reproduced these structural characteristics. Membrane propensities of two amphipathic helices in the cytoplasmic domain are further compared here to understand better their complicated orientational behavior known from experiment. This study first reveals that the highly conserved loop region in the cytoplasmic domain can be closely associated with the membrane surface. It is known from the simulation that Vpu is associated with 34 lipids in this Langmuir monolayer. The lipids that are located between the Vpu transmembrane helix and the first helix in the cytoplasmic domain are pushed up by Vpu. These elevated lipids have increased P-N tilt angles for the head groups but unchanged acyl-chain tilt angles compared with lipids that do not interact with Vpu. This study verifies the significance of applying MD simulation in refining protein structure and revealing detailed protein-lipid interaction in membrane/water environment. Figure XZ view of a snapshot of Vpu/DLGPC/water system after 3.5 ns NP(N)gamma T MD simulation. Coloring scheme: Vpu, red; C, green; H, pink; N, blue; O, orange; P, magenta; water, light blue     

A molecular dynamics simulation of the structure and properties of a self assembled monolayer formed from an amphiphilic polymer on a water surface

The polymer poly (3-octyl-3′-oxanoyl thiophene) has alternating hydrophobic octyl and hydrophilic oxanoyl side chains in the “3” positions of the thiophene rings, rendering it an interesting amphiphilic electro-active material. The application of compression on the amphiphilic polymer (which forms self-assembled monolayers (SAMs) on a water surface) is investigated by molecular dynamics (MDs). It is found that there is a range of surface pressures in which the material possesses lattice order. As the compression is increased beyond a critical value breakdown occurs leading to the rupture of the surface layer. The results of the dynamics are interpreted via atomic plots, atom-pair radial distribution functions (RDF), torsional distribution functions and by monitoring some of the dihedral angles as functions of time.     

Molecular dynamics simulations of trehalose as a 'dynamic reducer' for solvent water molecules in the hydration shell

Systematic computational work for a series of 13 disaccharides was performed to provide an atomic-level insight of unique biochemical role of the alpha,alpha-(1-->1)-linked glucopyranoside dimer over the other glycosidically linked sugars. Superior osmotic and cryoprotective abilities of trehalose were explained on the basis of conformational and hydration characteristics of the trehalose molecule. Analyses of the hydration number and radial distribution function of solvent water molecules showed that there was very little hydration adjacent to the glycosidic oxygen of trehalose and that the dynamic conformation of trehalose was less flexible than any of the other sugars due to this anisotropic hydration. The remarkable conformational rigidity that allowed trehalose to act as a sugar template was required for stable interactions with hydrogen-bonded water molecules. Trehalose made an average of 2.8 long-lived hydrogen bonds per each MD step, which was much larger than the average of 2.1 for the other sugars. The stable hydrogen-bond network is derived from the formation of long-lived water bridges at the expense of decreasing the dynamics of the water molecules. Evidence for this dynamic reduction of water by trehalose was also established based on each of the lowest translational diffusion coefficients and the lowest intermolecular coulombic energy of the water molecules around trehalose. Overall results indicate that trehalose functions as a 'dynamic reducer' for solvent water molecules based on its anisotropic hydration and conformational rigidity, suggesting that macroscopic solvent properties could be modulated by changes in the type of glycosidic linkages in sugar molecules.     

A molecular dynamics simulation study of the effect of water–graphene interaction on the properties of confined water

The role of water in determining the structure and stability of biomacromolecules has been well studied. In this work, molecular dynamics simulations have been applied to investigate the effect of surface hydrophobicity on the structure and dynamics of water confined between graphene surfaces. In order to evaluate this effect, we apply various attractive/repulsive water–graphene interaction potentials (hydrophobicity). The properties of confined water are studied by applying a purely repulsive interaction potential between water–graphene (modelled as a repulsive r^?12 potential) and repulsive–attractive forces (modelled as an LJ(12-6) potential). Compared to the case of a purely repulsive graphene–water potential, the inclusion of repulsive–attractive forces leads to formation of sharp peaks for density and the number of hydrogen bonds. Also, it was found that repulsive–attractive graphene–water potential caused slower hydrogen bonds dynamics and restricted the diffusion coefficient of water. Consequently, it was found that hydrogen bond breakage and formation rate with the repulsive r^?12 potential model, will increase compared to the corresponding water confined with the LJ(12-6) potential.     

Conformational Analysis of a Hybrid DNA-RNA Double Helical Oligonucleotide in Aqueous Solution: d(CG)r(CG)d(CG) Studied by 1D- and 2D-1H NMR Spectroscopy

Abstract

The double helical structure of the self-complementary DNA-RNA-DNA hybrid d(CG)r(CG) d(CG) was studied in solution by 500 MHz ¹H-NMR spectroscopy. The non-exchangeable base protons and the (deoxy)ribose H1′, H2′ and H2″ protons were unambiguously assigned using 2D-J-correlated (COSY) and 2D-NOE (NOESY) spectroscopy techniques. A general strategy for the sequential assignment of ¹H-NMR spectra of (double) helical DNA and RNA fragments by means of 2D-NMR methods is presented.

Conformational analysis of the sugar rings of d(CG)r(CG)d(CG) at 300 K shows that the central ribonucleotide part of the helix adopts an A-type double helical conformation. The 5′- and 3′-terminal deoxyribose base pairs, however, take up the normal DNA-type conformation. The A-to-B transition in this molecule involves only one (deoxyribose) base pair. It is shown that this A-to-B conformational transition can only be accomodated by two specific sugar pucker combinations for the junction base pair, i.e. N·S (C3′-endo-C2′-endo, 60%, where the pucker given first is that assigned to the junction nucleotide residue of the strand running 5′ → 3′ from A-RNA to B-DNA) and S·S (C2′-endo-C2′-endo, 40%).     

MMC and LD simulations of α-D-Glcp-(1→2)-α-D-Glcp-(1→3)-α-D-Glcp-OMe. A model for the terminal trisaccharide in glycoprotein precursors

The conformational flexibility and the dynamics of -D-Glcp-(12)--D-Glcp-(13)--D-Glcp-OMe (I) has been investigated by Metropolis-Monte Carlo with the HSEA (Hard Sphere Exo-Anomeric) force field and Langevin dynamics simulations employing two different CHARMm (Chemistry at HARvard Molecular Mechanics) force fields, CHEAT95 and PARM22. The conformational space spanned by the molecule is similar for the two former force fields but differ significantly for the latter. Hydrogen bonding between O2 and O4 of the title compound is analysed in comparison to NMR and preliminary results from X-ray powder diffraction studies. © 1998 Rapid Science Ltd     

Comparative structural dynamics of Tyrosyl-tRNA synthetase complexed with different substrates explored by molecular dynamics

Several molecular dynamics simulations of S. aureus Tyrosyl-tRNA synthetase (TyrRS) in its free form and complexed with Tyr, ATP, tyrosyl adenylate and inhibitor respectively have been carried out to investigate the ligand-linked conformational stability changes associated with its catalytic cycle. The results show that unliganded S. aureus TyrRS samples a more relaxed conformational space than substrate-bound TyrRS. There are three high flexibility regions encompassing residues 114–118, 128–133, and 226–238 respectively. The region which includes the KMSKS motif (KFGKS in S. aureus TyrRS) shows the highest difference in fluctuations. Hydrogen bond network formed by Tyr, ATP, tyrosyl adenylate and inhibitor with S. aureus TyrRS is discussed. Our simulations suggest the induced-fit conformational changes of the KMSKS loop as follows: the KMSKS loop of substrate-free S. aureus TyrRS adopts an open conformation. The tyrosine binds in the pocket with the KMSKS loop balancing between semi-open and open forms. The ATP binding induces the KMSKS loop to the open form. After the Tyr-AMP is formed, the first two residues of KMSKS loop twists in an anticlockwise direction and drives the loop in a conformation similar to the closed one, while those of the last three GKS residues adopt a conformation between semi-open and open conformation. This conformational change may probably be involved in the initial tRNA binding. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Sugar amino acids in designing new molecules

Emulating the basic principles followed by Nature to build its vast repertoire of biomolecules, organic chemists are developing many novel multifunctional building blocks and using them to create ‘nature-like’ and yet unnatural organic molecules. Sugar amino acids constitute an important class of such polyfunctional scaffolds where the carboxyl, amino and hydroxyl termini provide an excellent opportunity to organic chemists to create structural diversities akin to Nature’s molecular arsenal. This article describes some of our works on various sugar amino acids and many other related building blocks, like furan amino acids, pyrrole amino acids etc. used in wide-ranging peptidomimetic studies. Published in 2005.Based on the invited lecture presented at the XVII International Symposium on Glycoconjugates held in January 12–16, 2003 at Bangalore, India.     

The Stabilizing Effects of O-glycosylation on the Secondary Structural Integrity of the Designed α-loop-α motif by Molecular Dynamics Simulations

Abstract

In this study, various 400 ps molecular dynamics simulations were conducted to determine the stabilizing effect of O-glycosylation on the secondary structural integrity of the design α-loop-α motif, which has the optimal loop length of 7 Gly residues (denoted as N-A₁₆G₇A₁₆-C). In general, O-glycosylation stabilizes the structural integrity of the model peptide regardless of the length and position of glycosylation sites because it decreases the opportunity for water molecules to compete for the intramolecular hydrogen bonds. The designed peptide exhibits the highest helicity when residues 11 and 31 are replaced with Ser residues followed by O-linked with 3 galactose residues, representing the “face-to-face” glycosylation near the loop. In this case, the loop exhibits an extended conformation and several new hydrogen bonds are observed between the main chain of the loop and the galactose residues, resulting in decreasing the fluctuation and increasing the stability of the entire peptide. When the glycosylation are made close to the loop, the secondary structural integrity of the α-loop-α motif increases with the number of galactose residues. In addition, “face- to-face” glycosylation increases the structural integrity of this motif to a greater extent than “back-to-back” glycosylation. However, when the glycosylation are created away from the loop and near the N- and C-termini, no general rule is found for the stabilizing effect.