26 research outputs found
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Selective incorporation of proteinaceous over nonproteinaceous cationic amino acids in model prebiotic oligomerization reactions.
Numerous long-standing questions in origins-of-life research center on the history of biopolymers. For example, how and why did nature select the polypeptide backbone and proteinaceous side chains? Depsipeptides, containing both ester and amide linkages, have been proposed as ancestors of polypeptides. In this paper, we investigate cationic depsipeptides that form under mild dry-down reactions. We compare the oligomerization of various cationic amino acids, including the cationic proteinaceous amino acids (lysine, Lys; arginine, Arg; and histidine, His), along with nonproteinaceous analogs of Lys harboring fewer methylene groups in their side chains. These analogs, which have been discussed as potential prebiotic alternatives to Lys, are ornithine, 2,4-diaminobutyric acid, and 2,3-diaminopropionic acid (Orn, Dab, and Dpr). We observe that the proteinaceous amino acids condense more extensively than these nonproteinaceous amino acids. Orn and Dab readily cyclize into lactams, while Dab and Dpr condense less efficiently. Furthermore, the proteinaceous amino acids exhibit more selective oligomerization through their α-amines relative to their side-chain groups. This selectivity results in predominantly linear depsipeptides in which the amino acids are α-amine-linked, analogous to today's proteins. These results suggest a chemical basis for the selection of Lys, Arg, and His over other cationic amino acids for incorporation into proto-proteins on the early Earth. Given that electrostatics are key elements of protein-RNA and protein-DNA interactions in extant life, we hypothesize that cationic side chains incorporated into proto-peptides, as reported in this study, served in a variety of functions with ancestral nucleic acid polymers in the early stages of life
Comparison of CDMS [100] and [111] oriented germanium detectors
The Cryogenic Dark Matter Search (CDMS) utilizes large mass, 3" diameter
1" thick target masses as particle detectors. The target is
instrumented with both phonon and ionization sensors and comparison of energy
in each channel provides event-by-event classification of electron and nuclear
recoils. Fiducial volume is determined by the ability to obtain good phonon and
ionization signal at a particular location. Due to electronic band structure in
germanium, electron mass is described by an anisotropic tensor with heavy mass
aligned along the symmetry axis defined by the [111] Miller index (L valley),
resulting in large lateral component to the transport. The spatial distribution
of electrons varies significantly for detectors which have their longitudinal
axis orientations described by either the [100] or [111] Miller indices.
Electric fields with large fringing component at high detector radius also
affect the spatial distribution of electrons and holes. Both effects are
studied in a 3 dimensional Monte Carlo and the impact on fiducial volume is
discussed.Comment: Low Temperature Detector 14 conference proceedings to be published in
the Journal of Low Temperature Physic
Macrocyclic Peptoid–Peptide Hybrids as Inhibitors of Class I Histone Deacetylases
[Image: see text] We report the design, synthesis, and biological evaluation of the first macrocyclic peptoid-containing histone deacetylase (HDAC) inhibitors. The compounds selectively inhibit human class I HDAC isoforms in vitro, with no inhibition of the tubulin deacetylase activity associated with class IIb HDAC6 in cultured Jurkat cells. Compared to the natural product apicidin (1), one inhibitor (compound 10) showed equivalent potency against K-562 cells, but was more cytoselective across a panel of cancer cell lines
Discovery of HDAC Inhibitors That Lack an Active Site Zn<sup>2+</sup>-Binding Functional Group
Natural and synthetic histone deacetylase (HDAC) inhibitors
generally
derive their strong binding affinity and high potency from a key functional
group that binds to the Zn<sup>2+</sup> ion within the enzyme active
site. However, this feature is also thought to carry the potential
liability of undesirable off-target interactions with other metalloenzymes.
As a step toward mitigating this issue, here, we describe the design,
synthesis, and structure–activity characterizations of cyclic
α<sub>3</sub>β-tetrapeptide HDAC inhibitors that lack
the presumed indispensable Zn<sup>2+</sup>-binding group. The lead
compounds (e.g., <b>15</b> and <b>26</b>) display good
potency against class 1 HDACs and are active in tissue culture against
various human cancer cell lines. Importantly, enzymological analysis
of <b>26</b> indicates that the cyclic α<sub>3</sub>β-tetrapeptide
is a fast-on/off competitive inhibitor of HDACs 1–3 with <i>K</i><sub>i</sub> values of 49, 33, and 37 nM, respectively.
Our proof of principle study supports the idea that novel classes
of HDAC inhibitors, which interact at the active-site opening, but
not with the active site Zn<sup>2+</sup>, can have potential in drug
design
Templated Self-Assembly of Dynamic Peptide Nucleic Acids
Template-directed
macromolecule synthesis is a hallmark of living
systems. Inspired by this natural process, several fundamentally novel
mechanisms for template-directed assembly of nucleic acid analogues
have been developed. Although these approaches have broad significance,
including potential applications in biotechnology and implications
for the origins of life, there are unresolved challenges in how to
characterize in detail the complex assembly equilibria associated
with dynamic templated reactions. Here we describe mechanistic studies
of template-directed dynamic assembly for thioester peptide nucleic
acid (tPNA), an informational polymer that responds to selection pressures
under enzyme-free conditions. To overcome some of the inherent challenges
of mechanistic studies of dynamic oligomers, we designed, synthesized,
and implemented tPNA–DNA conjugates. The DNA primer region
affords a high level of control over the location and register of
the tPNA backbone in relation to the template strand. We characterized
the degree and kinetics of dynamic nucleobase mismatch correction
at defined backbone positions. Furthermore, we report the fidelity
of dynamic assembly in tPNA as a function of position along the peptide
backbone. Finally, we present theoretical studies that explore the
level of fidelity that can be expected for an oligomer having a given
hybridization affinity in dynamic templated reactions and provide
guidance for the future development of sequence self-editing polymers
and materials. As our results demonstrate, the use of molecular conjugates
of constitutionally static and dynamic polymers establishes a new
methodology for expediting the characterization of the complex chemical
equilibria that underlie the assembly of dynamic informational polymers
Macrocyclic Peptoid–Peptide Hybrids as Inhibitors of Class I Histone Deacetylases
We report the design, synthesis, and biological evaluation
of the
first macrocyclic peptoid-containing histone deacetylase (HDAC) inhibitors.
The compounds selectively inhibit human class I HDAC isoforms in vitro,
with no inhibition of the tubulin deacetylase activity associated
with class IIb HDAC6 in cultured Jurkat cells. Compared to the natural
product apicidin (<b>1</b>), one inhibitor (compound <b>10</b>) showed equivalent potency against K-562 cells, but was more cytoselective
across a panel of cancer cell lines