How well does molecular simulation reproduce environment-specific conformations of the intrinsically disordered peptides PLP,TP2 and ONEG?

Understanding the conformational ensembles of intrinsically disordered proteins and peptides (IDPs) in their various biological environments is essential for understanding their mechanisms and functional roles in the proteome, leading to a greater knowledge of, and potential treatments for, a broad range of diseases. To determine whether molecular simulation is able to generate accurate conformational ensembles of IDPs, we explore the structural landscape of the PLP peptide (an intrinsically disordered region of the proteolipid membrane protein) in aqueous and membrane-mimicking solvents, using replica exchange with solute scaling (REST2), and examine the ability of four force fields (ff14SB, ff14IDPSFF, CHARMM36 and CHARMM36m) to reproduce literature circular dichroism (CD) data. Results from variable temperature (VT) ¹H and Rotating frame Overhauser Effect SpectroscopY (ROESY) nuclear magnetic resonance (NMR) experiments are also presented and are consistent with the structural observations obtained from the simulations and CD. We also apply the optimum simulation protocol to TP2 and ONEG (a cell-penetrating peptide (CPP) and a negative control peptide, respectively) to gain insight into the structural differences that may account for the observed difference in their membrane-penetrating abilities. Of the tested force fields, we find that CHARMM36 and CHARMM36m are best suited to the study of IDPs, and accurately predict a disordered to helical conformational transition of the PLP peptide accompanying the change from aqueous to membrane-mimicking solvents. We also identify an α-helical structure of TP2 in the membrane-mimicking solvents and provide a discussion of the mechanistic implications of this observation with reference to the previous literature on the peptide. From these results, we recommend the use of CHARMM36m with the REST2 protocol for the study of environment-specific IDP conformations. We believe that the simulation protocol will allow the study of a broad range of IDPs that undergo conformational transitions in different biological environments.

A protocol for simulating intrinsically disordered peptides in aqueous and hydrophobic solvents is proposed. Results from four force fields are compared with experiment. CHARMM36m performs the best for the simulated IDPs in all environments.     

Addition of Me3SiCN to trifluoromethyl derivates of N‐(pyridylmethylidene) anilines catalyzed by Lewis acids

A series of novel Shiff bases (1a–h) was synthesized by condensation of pyridinecarboxaldehydes (1–4) with 3‐ and 4‐trifluoromethylanilines (5, 6) in the presence of molecular sieves (4 Å). It was found that AlCl₃ and AlBr₃ catalyzed the addition of Me₃SiCN to the C?N bond of the imines obtained, whereas the other Lewis acids studied (YCl₃, LaCl₃, ZnI₂) were not active. The reactivity of the imines in the title reaction, on the whole, correlated with their basicity. Besides the addition giving the expected α‐amino nitriles (2a,b,d–f,h), an unusual reaction leading to unsaturated nitriles (3a–h) was observed. The structures of saturated and unsaturated products 2d and 3c were determined by X‐ray diffraction. Copyright © 2001 John Wiley & Sons, Ltd.     

Adenine and thymine grafts on polyethyleneimine

Graft polymers of three different molecular weights of polyethyleneimine (PEI) with 9-(vinylsulfonylethyl) (9-VSE)-adenine and 1-(vinylsulfonylethyl) (1-VSE)-thymine were prepared. PEI's having molecular weights of 600, 1200, and 1800 were used and various ratios of VSE-nucleobases to ethyleneimine were employed in the grafting process. As expected, a decrease in the nucleobase substitution in the resulting graft polymer resulted in an increase in its water solubility. The degree of substitution in the graft polymers was calculated from sulfur determinations: in most cases this degree of substitution indicated that not all of the VSE derivative has reacted with the PEI due to the highly branched nature of the latter. The presence of nucleobase stacking in the polymers was studied by UV spectroscopy. Stacking was observed for the adenine polymers in both DMSO and 0.1N HCl while stacking in the thymine polymers was observed in 0.1N HCl but not in DMSO. The absence of stackingwithin the thymine polymers in DMSO was attributed to complexation of primary amino groups of the PEI backbone with the pyrimidine ring.