Search results for "molecular dynamics"
showing 10 items of 1075 documents
Reasons for the exclusive formation of heterodimeric capsules between tetra-tolyl and tetra-tosylurea calix[4]arenes
2007
The selective heterodimerization of tetra-tolyl (1a) and tetra-tosylurea (1b) calixarenes, serendipitously found by Rebek et al. (R. K. Castellano, B. H. Kim and J. Rebek, Jr., J. Am. Chem. Soc., 1997, 119, 12671–12672), has been used for the construction of highly sophisticated macrocycles and well-defined supramolecular assemblies. Regrettably, hitherto, neither the exact structure of these heterodimers nor the reason for their exclusive formation is known. We present molecular dynamics simulations using the AMBER force field in explicit chloroform solvent for the two homodimers, the heterodimer and the two uncomplexed tetra-urea calixarenes. The rigid rotation about the C–S–N–C bond of t…
Synthesis, in vitro activity, and three-dimensional quantitative structure-activity relationship of novel hydrazine inhibitors of human vascular adhe…
2010
Vascular adhesion protein-1 (VAP-1) belongs to the semicarbazide-sensitive amine oxidases (SSAOs) that convert amines into aldehydes. SSAOs are distinct from the mammalian monoamine oxidases (MAOs), but their substrate specificities are partly overlapping. VAP-1 has been proposed as a target for anti-inflammatory drug therapy because of its role in leukocyte adhesion to endothelium. Here, we describe the synthesis and in vitro activities of novel series of VAP-1 selective inhibitors. In addition, the molecular dynamics simulations performed for VAP-1 reveal that the movements of Met211, Ser496, and especially Leu469 can enlarge the ligand-binding pocket, allowing larger ligands than those s…
Delivery modulation in silica mesoporous supports via alkyl chain pore outlet decoration
2012
This article focuses on the study of the release rate in a family of modified silica mesoporous supports. A collection of solids containing ethyl, butyl, hexyl, octyl, decyl, octadecyl, docosyl, and triacontyl groups anchored on the pore outlets of mesoporous MCM-41 has been prepared and characterized. Controlled release from pore voids has been studied through the delivery of the dye complex tris(2,2¿-bipyridyl)ruthenium(II). Delivery rates were found to be dependent on the alkyl chain length anchored on the pore outlets of the mesoporous scaffolding. Moreover, release rates follow a Higuchi diffusion model, and Higuchi constants for the different hybrid solids have been calculated. A decr…
Structure, interdomain dynamics, and pH-dependent autoactivation of pro-rhodesain, the main lysosomal cysteine protease from African trypanosomes
2021
AbstractRhodesain is the lysosomal cathepsin L-like cysteine protease ofT. brucei rhodesiense, the causative agent of Human African Trypanosomiasis. The enzyme is essential for the proliferation and pathogenicity of the parasite as well as its ability to overcome the blood-brain barrier of the host. Lysosomal cathepsins are expressed as zymogens with an inactivating pro-domain that is cleaved under acidic conditions. A structure of the uncleaved maturation intermediate from a trypanosomal cathepsin L-like protease is currently not available. We thus established the heterologous expression ofT. brucei rhodesiensepro-rhodesain inE. coliand determined its crystal structure. The trypanosomal pr…
A Computational Study of the Protein-Ligand Interactions in CDK2 Inhibitors: Using Quantum Mechanics/Molecular Mechanics Interaction Energy as a Pred…
2006
ABSTRACT: We report a combined quantum mechanics/molecular mechanics (QM/MM) study to determine the protein-ligand interaction energy between CDK2 (cyclin-dependent kinase 2) and five inhibitors with the N2 -substituted 6-cyclohexylmethoxypurine scaffold. The computational results in this work show that the QM/MM interaction energy is strongly correlated to the biological activity and can be used as a predictor, at least within a family of substrates. A detailed analysis of the protein-ligand structures obtained from molecular dynamics simulations shows specific interactions within the active site that, in some cases, have not been reported before to our knowledge. The computed interaction …
Theoretical study of the temperature dependence of dynamic effects in thymidylate synthase.
2010
A theoretical study of the temperature dependence of dynamic effects in the rate limiting step of the reaction catalyzed by thymidylate synthase is presented in this paper. From hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) optimizations of transition state structures within a fully flexible molecular model, free downhill molecular dynamics trajectories have been performed at four different temperatures. The analysis of the reactive and non-reactive trajectories in the enzyme environment has allowed us to study the geometric and electronic coupling between the substrate, the cofactor and the protein. The results show how the contribution of dynamic effects to the rate enhancement mea…
Self-assembly of semiflexible polymers confined to thin spherical shells
2018
Confinement effects are critical for stiff macromolecules in biological cells, vesicles, and other systems in soft matter. For these molecules, the competition between the packing entropy and the enthalpic cost of bending is further shaped by strong confinement effects. Through coarse-grained molecular dynamics simulations, we explore the self-assembly of semiflexible polymers confined in thin spherical shells for various chain lengths, chain stiffnesses, and shell thicknesses. Here, we focus on the case where the contour and persistence length of the polymers are comparable to the radius of the confining cavity. The range of ordered structures is analyzed using several order parameters to …
Collective properties of hydration: long range and specificity of hydrophobic interactions
1997
We report results of molecular dynamics (MD) simulations of composite model solutes in explicit molecular water solvent, eliciting novel aspects of the recently demonstrated, strong many-body character of hydration. Our solutes consist of identical apolar (hydrophobic) elements in fixed configurations. Results show that the many-body character of PMF is sufficiently strong to cause 1) a remarkable extension of the range of hydrophobic interactions between pairs of solute elements, up to distances large enough to rule out pairwise interactions of any type, and 2) a SIF that drives one of the hydrophobic solute elements toward the solvent rather than away from it. These findings complement re…
Solution structure of aD,L-alternating oligonorleucine as a model of double-stranded antiparallel ?-helix
2002
Conformational characteristics of alternating D,L linear peptides are of particular interest because of their capacity to form transmembrane channels with different transport properties, as some natural antibiotics do. Single- and double-stranded beta-helical structures are common for alternating D,L peptides. The stability of the beta-helix depends on several structural factors, such as the backbone peptide length, type and position of side chains, and nature of terminal groups. The NMR and molecular dynamics solution conformation of a synthetic alternating D,L-oligopeptide with 15 norleucines (XVMe) has been used as a model to get insight in to the conformational features of double-strand…
Molecular dynamics of discotic charge-transfer complexes, dielectric spectroscopy and2H NMR studie
1994
Abstract Using a combination of solid state 2H NMR spectroscopy on selectively deuteriated samples and dielectric spectroscopy, the molecular dynamics of discotic charge-transfer (CT) complexes were investigated. These complexes show particular thermodynamic and flow properties. Considered were mixtures of low molar mass donors and acceptors, low molar mass donors with main chain acceptor polymers and covalently linked donor-acceptor twins with different lengths of the spacer. A main result is that correlated rotational motions of discotic molecules or groups about the columnar axis are observed in all systems except for the twin with the short spacer. This type of motion seems to be a gene…