We present a method and web server for predicting DNA structural features in a high-throughput (HT) manner for massive sequence data. This approach provides the framework for the integration of DNA sequence and shape analyses in genome-wide studies. The HT methodology uses a sliding-window approach to mine DNA structural information obtained from Monte Carlo simulations. It requires only nucleotide sequence as input and instantly predicts multiple structural features of DNA (minor groove width, roll, propeller twist and helix twist). The results of rigorous validations of the HT predictions based on DNA structures solved by X-ray crystallography and NMR spectroscopy, hydroxyl radical cleavage data, statistical analysis and cross-validation, and molecular dynamics simulations provide strong confidence in this approach. The DNAshape web server is freely available at http://rohslab.cmb.usc.edu/DNAshape/.

DNA binding proteins find their cognate sequences within genomic DNA through recognition of specific chemical and structural features. Here we demonstrate that high-resolution DNase I cleavage profiles can provide detailed information about the shape and chemical modification status of genomic DNA. Analyzing millions of DNA backbone hydrolysis events on naked genomic DNA, we show that the intrinsic rate of cleavage by DNase I closely tracks the width of the minor groove. Integration of these DNase I cleavage data with bisulfite sequencing data for the same cell type’s genome reveals that cleavage directly adjacent to cytosine-phosphate-guanine (CpG) dinucleotides is enhanced at least eightfold by cytosine methylation. This phenomenon we show to be attributable to methylation-induced narrowing of the minor groove. Furthermore, we demonstrate that it enables simultaneous mapping of DNase I hypersensitivity and regional DNA methylation levels using dense in vivo cleavage data. Taken together, our results suggest a general mechanism by which CpG methylation can modulate protein–DNA interaction strength via the remodeling of DNA shape.

Aggregation of the full‐length amyloid‐β (Aβ) and β2‐microglobulin (β2m) proteins is associated with Alzheimer's disease and dialysis‐related amyloidosis, respectively. This assembly process is not restricted to full‐length proteins, however, many short peptides also assemble into amyloid fibrils in vitro. Remarkably, the kinetics of amyloid‐fibril formation of all these molecules is generally described by a nucleation‐polymerization process characterized by a lag phase associated with the formation of a nucleus, after which fibril elongation occurs rapidly. In this study, we report using long molecular dynamics simulations with the OPEP coarse‐grained force field, the thermodynamics and dynamics of the octamerization for two amyloid 7‐residue peptides: the β2m83‐89 NHVTLSQ and Aβ16‐22 KLVFFAE fragments. Based on multiple trajectories run at 310 K, totaling 2.2 μs (β2m83‐89) and 4.8 μs (Aβ16‐22) and starting from random configurations and orientations of the chains, we find that the two peptides not only share common but also very different aggregation properties. Notably, an increase in the hydrophobic character of the peptide, as observed in Aβ16‐22 with respect to β2m83‐89 impacts the thermodynamics by reducing the population of bilayer β‐sheet assemblies. Higher hydrophobicity is also found to slow down the dynamics of β‐sheet formation by enhancing the averaged lifetime of all configuration types (CT) and by reducing the complexity of the CT transition probability matrix. Proteins 2009.

The human islet amyloid polypeptide (hIAPP) or amylin is a 37-residue hormone found as amyloid deposits in pancreatic extracts of nearly all type 2 diabetes patients. The fragment 20–29 of sequence SNNFGAILSS (hIAPP20–29) has been shown to be responsible for the amyloidogenic propensities of the full length protein. Various polymorphic forms of hIAPP20–29 fibrils were described by using Fourier transform infrared (FTIR) and solid-state NMR experiments: unseeded hIAPP20–29 fibril with out-of-register antiparallel β-strands, and two forms of seeded hIAPP20–29 fibril, with in-register antiparallel or in-register parallel β-strands. As a first step toward understanding this polymorphism, we explore the equilibrium structures of the soluble hIAPP20–29 trimer, using multiple molecular dynamics (MD) simulations with the Optimized Potential for Efficient structure Prediction (OPEP) coarse-grained implicit solvent force field for a total length of 3.2 μs. Although, the trimer is found mainly random coil, consistent with the signal measured experimentally during the lag phase of hIAPP20–29 fibril formation, the central FGAIL residues have a relative high propensity to form interpeptide β-sheets and antiparallel β-strands are more probable than parallel β-strands. One MD-predicted out-of-register antiparallel three-stranded β-sheet matches exactly the FTIR-derived unseeded hIAPP20–29 fibril model. Our simulations, however, do not reveal any evidence of in-register parallel or in-register antiparallel β-sheets as reported for seeded hIAPP20–29 fibrils. All these results indicate that fibril polymorphism is partially encoded in a trimer.