Graphical abstract

Previously, it has been reported that human telomeric DNA sequences could adopt in different experimental conditions four different intramolecular G-quadruplexes each involving three G-tetrad layers, namely Na + -solution antiparallel-stranded basket form, K + -crystal parallel-stranded propeller form, K + -solution (3+1) Form 1 and K + -solution (3+1) Form 2. Here we present a new intramolecular G-quadruplex adopted by a four-repeat human telomeric sequence in K + solution (Form 3). This structure is a basket-type G-quadruplex with only two G-tetrad layers: loops are successively edgewise, diagonal and edgewise; glycosidic conformations of guanines are syn•syn•anti•anti around each tetrad; each strand of the core has both a parallel and an antiparallel adjacent strands; there are one narrow, one wide and two medium grooves. Despite the presence of only two G-tetrads in the core, this structure is more stable than the three-G-tetrad intramolecular G-quadruplexes previously observed for human telomeric sequences in K + solution. Detailed structural elucidation of Form 3 revealed extensive base pairing and stacking in the loops capping both ends of the G-tetrad core, which might explain the high stability of the structure. This novel structure highlights the conformational heterogeneity of human telomeric DNA. It revealed a new folding principle for Gquadruplexes and suggests new loop sequences and structures for targeting in human telomeric DNA.

A 100 ns molecular dynamics simulation of penta-alanine in explicit water is performed to study the reversible folding and unfolding of the peptide. Employing a standard principal component analysis (PCA) using Cartesian coordinates, the resulting free-energy landscape is found to have a single minimum, thus suggesting a simple, relatively smooth free-energy landscape. Introducing a novel PCA based on a transformation of the peptide dihedral angles, it is found, however, that there are numerous free energy minima of comparable energy (less than or approximately 1 kcal/mol), which correspond to well-defined structures with characteristic hydrogen-bonding patterns. That is, the true free-energy landscape is actually quite rugged and its smooth appearance in the Cartesian PCA represents an artifact of the mixing of internal and overall motion. Well-separated minima corresponding to specific conformational structures are also found in the unfolded part of the free energy landscape, revealing that the unfolded state of penta-alanine is structured rather than random. Performing a connectivity analysis, it is shown that neighboring states are connected by low barriers of similar height and that each state typically makes transitions to three or four neighbor states. Several principal pathways for helix nucleation are identified and discussed in some detail.

Nonlinear time-resolved vibrational spectroscopy is used to compare spectral broadening of the amide I band of the small peptide trialanine with that of N-methylacetamide, a commonly used model system for the peptide bond. In contrast to N-methylacetamide, the amide I band of trialanine is significantly inhomogeneously broadened. Employing classical molecular-dynamics simulations combined with density-functional-theory calculations, the origin of the spectral inhomogeneity is investigated. While both systems exhibit similar hydrogen-bonding dynamics, it is found that the conformational dynamics of trialanine causes a significant additional spectral broadening. In particular, transitions between the poly͑Gly͒II and the ␣ R conformations are identified as the main source of the additional spectral inhomogeneity of trialanine. The experimental and computational results suggest that trialanine adopts essentially two conformations: poly͑Gly͒II ͑80%͒ and ␣ R ͑20%͒. The potential of the joint experimental and computational approach to explore conformational dynamics of peptides is discussed.

No abstract

Growing evidence supports that amyloid β (Aβ) oligomers are the major causative agents leading to neural cell death in Alzheimer's disease. The polyphenol (-)-epigallocatechin gallate (EGCG) was recently reported to inhibit Aβ fibrillization and redirect Aβ aggregation into unstructured, off-pathway oligomers. Given the experimental challenge to characterize the structures of Aβ/EGCG complexes, we performed extensive atomistic replica exchange molecular dynamics simulations of Aβ1-42 dimer in the present and absence of EGCG in explicit solvent. Our equilibrium Aβ dimeric structures free of EGCG are consistent with the collision cross section from ion-mobility mass spectrometry and the secondary structure composition from circular dichroism experiment. In the presence of EGCG, the Aβ structures are characterized by increased inter-center-of-mass distances, reduced interchain and intrachain contacts, reduced β-sheet content, and increased coil and α-helix contents. Analysis of the free energy surfaces reveals that the Aβ dimer with EGCG adopts new conformations, affecting therefore its propensity to adopt fibril-prone states. Overall, this study provides, for the first time, insights on the equilibrium structures of Aβ1-42 dimer in explicit aqueous solution and an atomic picture of the EGCG-mediated conformational change on Aβ dimer.

Computational drug discovery provides an efficient tool for helping large-scale lead molecule screening. One of the major tasks of lead discovery is identifying molecules with promising binding affinities toward a target, a protein in general. The accuracies of current scoring functions that are used to predict the binding affinity are not satisfactory enough. Thus, machine learning or deep learning based methods have been developed recently to improve the scoring functions. In this study, a deep convolutional neural network model (called OnionNet) is introduced; its features are based on rotation-free element-pair-specific contacts between ligands and protein atoms, and the contacts are further grouped into different distance ranges to cover both the local and nonlocal interaction information between the ligand and the protein. The prediction power of the model is evaluated and compared with other scoring functions using the comparative assessment of scoring functions (CASF-2013) benchmark and the v2016 core set of the PDBbind database. The robustness of the model is further explored by predicting the binding affinities of the complexes generated from docking simulations instead of experimentally determined PDB structures.

Driven by recent two-dimensional infrared experiments by Woutersen and Hamm, trialanine has emerged as a paradigm to study conformational dynamics of a small peptide in aqueous solution. Employing the exceptional amount of experimental and ab initio data, in this work, trialanine serves as a model problem to perform a comprehensive comparison of six popular force fields, including the recent versions of the AMBER, CHARMM, GROMOS, and OPLS models. For all force fields under consideration, 20 ns long molecular-dynamics simulations are performed, and the structure and conformational dynamics of the solvated peptide is studied in detail. Employing density-functional theory calculations at the B3LYP/6-31+G(d) level, a number of observable quantities are calculated directly from the molecular-dynamics data and compared to experiment. The comparison allows for a quite detailed interpretation of recent NMR and infrared experiments. The nowadays achievable reliability and accuracy of a molecular dynamics description of a highly flexible biomolecular system are discussed in some detail.