Biomedical subjects

Hui-Hsu Gavin Tsai

Publications and source records attributed to Hui-Hsu Gavin Tsai.

6 recordsLinked to original sources

PubMed2006

Probing the intrachain and interchain effects on the fluorescence behavior of pentiptycene-derived oligo(p-phenyleneethynylene)s.

The synthesis, crystal structure, and fluorescence behavior of acetylene-bridged pentiptycene dimer (2), trimer (3), and tetramer (4) are reported. For comparison, a phenylene-pentiptycene-phenylene three-ring system (5) is also investigated. As a result of the unique intrachain pentiptycene-pentiptycene interactions in 3 and 4, their twisted conformers are populated in polar solvents and at low temperatures, and the phenomenon of nonequilibration of excited rotational conformers is observed. Twisting of the pi-conjugated backbones leads to blue-shifted absorption and fluorescence spectra and increased fluorescence quantum yields and lifetimes. The fluorescence spectra of 2-4 undergo small red shifts but large intensity variations in the 0-1 vs 0-0 bands on going from solutions to thin solid films, which can be accounted for by the reabsorption effect. However, the reduction in fluorescence quantum yields for 2-4 in films vs solutions is mainly attributed to efficient interchain exciton migration to nonfluorescent energy traps. In contrast, the behavior of nonequilibration of excited rotamers is not observed for 5 in solutions. Compound 5 forms J-type aggregates through terminal phenylene pi-stackings in the solid state, resulting in a new absorption band at 377 nm and large red shifts of the structured fluorescence spectra.

Journal Article↗

PubMed2006

Sequence and structure analysis of parallel beta helices: implication for constructing amyloid structural models.

Increasing evidence suggests that amyloids and parallel beta helices may share similar motifs. A systemic analysis of beta helices is performed to examine their sequence and structural characteristics. Ile prefers to occur in beta strands. In contrast, Pro is disfavored, compatible with the underlying assumption in Pro-scanning mutagenesis. Cys, Asn, and Phe form significant homostacking (identical amino acid interactions). Asn is highly conserved in the high-energy, left-handed alpha-helical conformation, where it frequently forms amide stacking. Based on the observed prominent stacking of chemically similar residues in parallel beta helices, we propose that within the "cross-beta" framework, amyloids with longer peptide chains may have common structural features of in-register, parallel alignment, with the side chains forming identical amino acid ladders. The requirement of ladder formation limits the combinations of side chain interactions. Such a limit combined with environmental conditions (e.g., pH, concentration) could be a major reason for the ability of most polypeptides to form amyloids.

Amino Acid Sequence↗

PubMed2005

Energy landscape of amyloidogenic peptide oligomerization by parallel-tempering molecular dynamics simulation: significant role of Asn ladder.

Recent evidence suggests that amyloidogenic oligomers may be the toxic species in cell cultures. Thus, it is crucial to understand their structure and oligomerization mechanism in atomistic detail. By employing tens of fast central processing units and an advanced phase-space sampling algorithm, parallel-tempering molecular dynamics, we have explored the energy landscape of amyloidogenic peptide oligomerization in explicit water. A pentapeptide, DFNKF, derived from human calcitonin and its mutant, DFAKF, was simulated with a total simulation time of approximately 500 ns. The detailed oligomerization process of a DFNKF parallel beta-sheet formation at 300 K has been characterized. The assembly of a parallel beta-sheet from the amorphous state mainly occurs via a "bottleneck" channel where the interstrand Asn-Asn stacking is the major interaction. The interactions of Asn-Asn stacking include both backbone and side-chain hydrogen bonds. The Asn-Asn interactions work like "glue" by sticking the DFNKF strands together and assist the "on-pathway" oligomerization. The Asn-Asn stacking observed here is similar to the Asn ladder commonly found in globular beta-helix proteins. A control run shows that when Asn is mutated to Ala, the stability and population of the DFAKF parallel beta-sheet is decreased. Furthermore, our in vitro mutagenesis experiments show that the ability of DFAKF peptides to form amyloid fibrils is significantly reduced, in agreement with the simulations. Knowledge of the energy landscape of oligomerization may provide hints for rational drug design, preventing amyloid-associated diseases.

Algorithms↗

PubMed2004

Insights into amyloid structural formation and assembly through computational approaches.

Amyloids are long, insoluble ordered fibers. Due to their insolubility, to date the determination of an amyloid structure with an atomic scale resolution has proven to be a difficult task. Under such circumstances, computational approaches are a preferred option, providing the means to build likely models, test their stabilities and figure out the chemistry of their prevailing interactions. Computational models can be validated by targeted experiments, such as introducing mutations and testing for amyloid formation. Computations further provide vehicles for the comprehension of the mechanisms of amyloid seed formation and oligomer toxicity. Nevertheless, computations face an immense hurdle, the outcome of the time scales involved in amyloid formation and the immense sizes of the systems. In an attempt to overcome these, we adopt a strategy that encompasses (1) bioinformatics studies of native proteins containing beta-sheet structures; (2) simulations of shorter peptides; and finally (3) construction of potential oligomeric models and tests of their stabilities. The results are correlated with experimental data where available. Here, we describe the computational methods in simple terms and present an overview of the results. The systems derive from amyloidogenic, disease-related proteins, including gelsolin, beta2-microglobulin, and peptides derived from the prion, Alzheimer's Abeta, IAPP and human calcitonin. Ultimately, obtaining molecular structures should facilitate efforts to therapy and drug design.

Amyloid↗

PubMed2004

Side chain interactions determine the amyloid organization: a single layer beta-sheet molecular structure of the calcitonin peptide segment 15-19.

In this paper we present a detailed atomic model for a protofilament, the most basic organization level, of the amyloid fibre formed by the peptide DFNKF. This pentapeptide is a segment derived from the human calcitonin, a natural amyloidogenic protein. Our model, which represents the outcome of extensive explicit solvent molecular dynamics (MD) simulations of different strand/sheet organizations, is a single beta-sheet filament largely without a hydrophobic core. Nevertheless, this structure is capable of reproducing the main features of the characteristic amyloid fibril organization and provides clues to the molecular basis of its experimental aggregation behaviour. Our results show that the side chains' chemical diversity induces the formation of a complex network of interactions that finally determine the microscopic arrangement of the strands at the protofilament level. This network of interactions, consisting of both side chain-side chain and backbone-side chain interactions, confers on the final single beta-sheet arrangement an unexpected stability, both by enhancing the association of related chemical groups and, at the same time, by shielding the hydrophobic segments from the polar solvent. The chemical physical characterization of this protofilament provides hints to the possible thermodynamical basis of the supra molecular organization that allows the formation of the filaments by lateral association of the preformed protofibrils. Its regular, highly polarized structure shows how other protofilaments can assemble. In terms of structural biology, our results clearly indicate that an amyloid organization implies a degree of complexity far beyond a simple nonspecific association of peptide strands via amide hydrogen bonds.

Amino Acid Sequence↗

PubMed2004

In silico protein design by combinatorial assembly of protein building blocks.

Utilizing concepts of protein building blocks, we propose a de novo computational algorithm that is similar to combinatorial shuffling experiments. Our goal is to engineer new naturally occurring folds with low homology to existing proteins. A selected protein is first partitioned into its building blocks based on their compactness, degree of isolation from the rest of the structure, and hydrophobicity. Next, the protein building blocks are substituted by fragments taken from other proteins with overall low sequence identity, but with a similar hydrophobic/hydrophilic pattern and a high structural similarity. These criteria ensure that the designed protein has a similar fold, low sequence identity, and a good hydrophobic core compared with its native counterpart. Here, we have selected two proteins for engineering, protein G B1 domain and ubiquitin. The two engineered proteins share approximately 20% and approximately 25% amino acid sequence identities with their native counterparts, respectively. The stabilities of the engineered proteins are tested by explicit water molecular dynamics simulations. The algorithm implements a strategy of designing a protein using relatively stable fragments, with a high population time. Here, we have selected the fragments by searching for local minima along the polypeptide chain using the protein building block model. Such an approach provides a new method for engineering new proteins with similar folds and low homology.

Amino Acid Sequence↗