Modeling large protein–glycosaminoglycan complexes using a fragment-based approach

Glycosaminoglycans (GAGs), a major constituent of the extracellular matrix, participate in cell-signaling by binding specific proteins. Structural data on protein–GAG interactions are crucial to understand and modulate these signaling processes, with potential applications in regenerative medicine. However, experimental and theoretical approaches used to study GAG–protein systems are challenged by GAGs high flexibility limiting the conformational sampling above a certain size, and by the scarcity of GAG-specific docking tools compared to protein–protein or protein–drug docking approaches. We present for the first time an automated fragment-based method for docking GAGs on a protein binding site. In this approach, trimeric GAG fragments are flexibly docked to the protein, assembled based on their spacial overlap, and refined by molecular dynamics. The method appeared more successful than the classical full-ligand approach for most of 13 tested complexes with known structure. The approach is particularly promising for docking of long GAG chains, which represents a bottleneck for classical docking approaches applied to these systems. © 2019 Wiley Periodicals, Inc.     

A Karplus Equation for the Conformational Analysis of Organic Molecular Crystals

Vicinal scalar couplings (³J) are extensively used for the conformational analysis of organic compounds in the liquid state through empirical Karplus equations. In contrast, there are no examples of such use for the structural investigation of solids. With the support of first principles calculations, we demonstrate here that ¹³C‐¹³C ³J coupling constants (³J_CC) measured on a series of isotopically enriched solid amino acids and sugars can be related to dihedral angles by a simple Karplus‐like relationship, and we provide a parameterized Karplus function for the conformational analysis of organic molecular crystals. Under the experimental conditions discussed, torsional angles can be estimated from the experimental ³J_CC values with an accuracy of 10° using this function. These results open new perspectives towards the use of ³J_CC as a new analytical tool that could considerably simplify structure determination of functional organic solids.     

Synthesis of branched poly(methyl methacrylate)s via controlled/living polymerisations exploiting ethylene glycol dimethacrylate as branching agent

With appropriate choice of reaction composition and conditions, copolymerisation of methyl methacrylate and ethylene glycol dimethacrylate using Cu-based ATRP or GTP methodologies yields soluble branched polymers in facile one-pot reactions.     

Conception and Evaluation of a Library of Cleavable Mass Tags for Digital Polymers Sequencing

A library of phosphoramidite monomers containing a main-chain cleavable alkoxyamine and a side-chain substituent of variable molar mass (i.e. mass tag) was prepared in this work. These monomers can be used in automated solid-phase phosphoramidite chemistry and therefore incorporated periodically as spacers inside digitally-encoded poly(phosphodiester) chains. Consequently, the formed polymers contain tagged cleavable sites that guide their fragmentation in mass spectrometry sequencing and enhance their digital readability. The spacers were all prepared via a seven steps synthetic procedure. They were afterwards tested for the synthesis and sequencing of model digital polymers. Uniform digitally-encoded polymers were obtained as major species in all cases, even though some minor defects were sometimes detected. Furthermore, the polymers were decoded in pseudo-MS³ conditions, thus confirming the reliability and versatility of the spacers library.