Non-commutative Geometry Modified Non-Gaussianities of Cosmological Perturbation

We investigate the noncommutative effect on the non-Gaussianities of primordial cosmological perturbation. In the lowest order of string length and slow-roll parameter, we find that in the models with small speed of sound the noncommutative modifications could be observable if assuming a relatively low string scale. In particular, the dominant modification of non-Gaussianity estimator f_{NL} could reach O(1) in DBI inflation and K-inflation. The corrections are sensitive to the speed of sound and the choice of string length scale. Moreover the shapes of the corrected non-Gaussianities are distinct from that of ordinary ones.Comment: 26 pages, 3 figures Added references, changed conten

Structural Basis of Caspase-3 Substrate Specificity Revealed by Crystallography, Enzyme Kinetics, and Computational Modeling

Caspase-3 is a cysteine protease that hydrolyzes diverse intracellular proteins during programmed cell death (known as apoptosis). It has been a popular target for drug design against abnormal cell death for more than a decade. No approved caspase based drug, however, is available so far. Therefore, structural insights about the substrate recognition of caspase-3 are needed for the future development of caspase-3 based inhibitors and drugs. In this study, crystal structures of recombinant caspase-3 in complex with seven substrate analog inhibitors, including acetyl (Ac)-DEVD-aldehyde (Cho), Ac-DMQD-Cho, Ac-IEPD-Cho, Ac-YVAD-Cho, Ac-WEHD-Cho, Ac-VDVAD-Cho, and tert-butoxycarbonyl (Boc)-D-fluoromethylketone (Fmk), have been analyzed in combination with enzyme kinetic data and computational models. Seven crystal structures were determined at resolutions of 1.7-2.6Å. The binding conformation of each inhibitor residue at P1-P4 position was analyzed. The negative P1 aspartic acid side chain is exclusively required by the positive S1 pocket of caspase-3. Small hydrophobic P2 residues are preferred by the nonpolar S2 pocket formed by Y204, W206, and F256. Although hydrophilic residues at P3 position tend to fit better, hydrophobic residues also can be accommodated by the plastic S3 pocket. Two substrate binding sites were found in the S4 pocket, one formed by main chain atoms of F250 and side chain atoms of N208 and the other formed by aromatic side chains of W206 and W214. These two binding sites are responsible for the binding of hydrophilic and hydrophobic P4 residues, respectively. Furthermore, the S5 subsite of caspase-3 formed by side chains of F250 and F252 was discovered. It stabilizes hydrophobic P5 residues on the substrates by an induced fit mechanism. Computational studies were performed to help improve prediction of protein structures and protein-ligand interactions. Based on the Morse’s function, a novel potential function with only three adjustable parameters per residue pair was developed, which will significantly increase the efficiency of protein structure prediction and molecular mechanics. Altogether, our studies have provided valuable information for the future caspase-3 based drug development