Combinatorial Pattern Discovery Approach for the Folding Trajectory Analysis of a β-Hairpin

The study of protein folding mechanisms continues to be one of the most challenging problems in computational biology. Currently, the protein folding mechanism is often characterized by calculating the free energy landscape versus various reaction coordinates, such as the fraction of native contacts, the radius of gyration, RMSD from the native structure, and so on. In this paper, we present a combinatorial pattern discovery approach toward understanding the global state changes during the folding process. This is a first step toward an unsupervised (and perhaps eventually automated) approach toward identification of global states. The approach is based on computing biclusters (or patterned clusters)—each cluster is a combination of various reaction coordinates, and its signature pattern facilitates the computation of the Z-score for the cluster. For this discovery process, we present an algorithm of time complexity c∈RO((N + nm) log n), where N is the size of the output patterns and (n × m) is the size of the input with n time frames and m reaction coordinates. To date, this is the best time complexity for this problem. We next apply this to a β-hairpin folding trajectory and demonstrate that this approach extracts crucial information about protein folding intermediate states and mechanism. We make three observations about the approach: (1) The method recovers states previously obtained by visually analyzing free energy surfaces. (2) It also succeeds in extracting meaningful patterns and structures that had been overlooked in previous works, which provides a better understanding of the folding mechanism of the β-hairpin. These new patterns also interconnect various states in existing free energy surfaces versus different reaction coordinates. (3) The approach does not require calculating the free energy values, yet it offers an analysis comparable to, and sometimes better than, the methods that use free energy landscapes, thus validating the choice of reaction coordinates. (An abstract version of this work was presented at the 2005 Asia Pacific Bioinformatics Conference [1].

Large Domain Motions in Ago Protein Controlled by the Guide DNA-Strand Seed Region Determine the Ago-DNA-mRNA Complex Recognition Process

The recognition mechanism and cleavage activity of argonaute (Ago), miRNA, and mRNA complexes are the core processes to the small non-coding RNA world. The 5′ nucleation at the ‘seed’ region (position 2–8) of miRNA was believed to play a significant role in guiding the recognition of target mRNAs to the given miRNA family. In this paper, we have performed all-atom molecular dynamics simulations of the related and recently revealed Ago-DNA:mRNA ternary complexes to study the dynamics of the guide-target recognition and the effect of mutations by introducing “damaging” C·C mismatches at different positions in the seed region of the DNA-RNA duplex. Our simulations show that the A-form-like helix duplex gradually distorts as the number of seed mismatches increases and the complex can survive no more than two such mismatches. Severe distortions of the guide-target heteroduplex are observed in the ruinous 4-sites mismatch mutant, which give rise to a bending motion of the PAZ domain along the L1/L2 “hinge-like” connection segment, resulting in the opening of the nucleic-acid-binding channel. These long-range interactions between the seed region and PAZ domain, moderated by the L1/L2 segments, reveal the central role of the seed region in the guide-target strands recognition: it not only determines the guide-target heteroduplex’s nucleation and propagation, but also regulates the dynamic motions of Ago domains around the nucleic-acid-binding channel

UV-radiation Induced Disruption of Dry-Cavities in Human γD-crystallin Results in Decreased Stability and Faster Unfolding

Age-onset cataracts are believed to be expedited by the accumulation of UV-damaged human γD-crystallins in the eye lens. Here we show with molecular dynamics simulations that the stability of γD-crystallin is greatly reduced by the conversion of tryptophan to kynurenine due to UV-radiation, consistent with previous experimental evidences. Furthermore, our atomic-detailed results reveal that kynurenine attracts more waters and other polar sidechains due to its additional amino and carbonyl groups on the damaged tryptophan sidechain, thus breaching the integrity of nearby dry center regions formed by the two Greek key motifs in each domain. The damaged tryptophan residues cause large fluctuations in the Tyr-Trp-Tyr sandwich-like hydrophobic clusters, which in turn break crucial hydrogen-bonds bridging two β-strands in the Greek key motifs at the “tyrosine corner”. Our findings may provide new insights for understanding of the molecular mechanism of the initial stages of UV-induced cataractogenesis.International Business Machines Corporation (IBM Blue Gene Program