Hong-Yu Zhang

Distribution patterns of small-molecule ligands in the protein universe and implications for origin of life and drug discovery

BackgroundExtant life depends greatly on the binding of small molecules (such as ligands) with macromolecules (such as proteins), and one ligand can bind multiple proteins. However, little is known about the global patterns of ligand-protein mapping.ResultsBy examining 2,186 well-defined small-molecule ligands and thousands of protein domains derived from a database of druggable binding sites, we show that a few ligands bind tens of protein domains or folds, whereas most ligands bind only one, which indicates that ligand-protein mapping follows a power law. Through assigning the protein-binding orders (early or late) for bio-ligands, we demonstrate that the preferential attachment principle still holds for the power-law relation between ligands and proteins. We also found that polar molecular surface area, H-bond acceptor counts, H-bond donor counts and partition coefficient are potential factors to discriminate ligands from ordinary molecules and to differentiate super ligands (shared by three or more folds) from others.ConclusionThese findings have significant implications for evolution and drug discovery. First, the chronology of ligand-protein binding can be inferred by the power-law feature of ligand-protein mapping. Some nucleotide-containing ligands, such as ATP, ADP, GDP, NAD, FAD, dihydro-nicotinamide-adenine-dinucleotide phosphate (NDP), nicotinamide-adenine-dinucleotide phosphate (NAP), flavin mononucleotide (FMN) and AMP, are found to be the earliest cofactors bound to proteins, agreeing with the current understanding of evolutionary history. Second, the finding that about 30% of ligands are shared by two or more domains will help with drug discovery, such as in finding new functions from old drugs, developing promiscuous drugs and depending more on natural products.

A Theoretical Elucidation on the Solvent-dependent Photosensitive Behaviors of C60

Abstract In this paper, the solvent-dependent photosensitive behaviors of fullerene (C60) were investigated in polar and nonpolar solvents by time-dependent density functional theory (TD-DFT) calculation. Based on the calculated physicochemical parameters on triplet state, it is revealed that excited-state C60 only generates 1O2 via energy transfer in benzene, but can give birth to O2·− and 1O2 in water via energy transfer and electron transfer, respectively. Considering the fact that electron transfer is more favorable compared with energy transfer in polar biological systems, especially with the presence of electron donors, the O2·−-generating process will get predominant in physiological systems. These results account well for the experimental observations that O2·− and ·OH are primarily responsible for the photoinduced DNA cleavage by C60 under physiological conditions, whereas 1O2 plays a critical role in nonpolar solvents.

Why Is the C-terminus of Aβ(1-42) More Unfolded than That of Aβ(1-40)? Clues from Hydrophobic Interaction

Abeta(1-40) and Abeta(1-42) are the main forms of amyloid beta (Abeta) peptides in the brain of Alzheimers patients; however, the latter possesses much stronger aggregation and deposition propensity than the former, which is partially attributed to the more unfolded C-terminus of Abeta(1-42) than that of Abeta(1-40). To explore the physical basis underlying the different dynamic behaviors of both Abeta peptides, parallel molecular dynamics (MD) simulations on Abeta(1-40) and Abeta(1-42) were performed to investigate their thermal unfolding processes. It is revealed that the addition of residues 41 and 42 in Abeta(1-42) disrupts the C-terminal hydrophobic core, which triggers the unraveling of the C-terminal helix of Abeta(1-42). This conclusion is supported by the MD simulation on the I41A mutant of Abeta(1-42), in which the C-terminal helix possesses relatively higher conformational stability than that of wild type Abeta(1-42) owing to the change in hydrophobic interaction patterns.

A comparison of the excited-state processes of nearly symmetrical perylene quinones: hypocrellin A and hypomycin B

Abstract The excited-state photophysics of two naturally occurring nearly symmetrical perylene quinones are discussed: hypocrellin A and hypomycin B. Hypocrellin A has a hydroxyl group peri to a carbonyl group on either end of its long molecular axis in addition to a hydroxyl group on its seven-membered ring. On the other hand, hypomycin B is unique among this class of known naturally occurring perylene quinones in that it possesses only one hydroxyl group, which is peri to a carbonyl group. These quinones are investigated in different nonionic micellar environments. For hypocrellin A and hypomycin B, a micelle concentration 10 times in excess of that used for hypericin in a previous study, i.e. 100 times the critical micelle concentration, must be employed to obviate aggregation. Under such conditions, the p K a of the peri hydroxyl groups of hypocrellin A have been determined to be 8.9. The p K a of the protonated carbonyl groups could not be measured. A comparable value is estimated for hypomycin B. The differing solubilities and behaviors of hypericin and hypocrellin in micellar environments are briefly discussed in the context of their biological activity. The excited-state processes in hypocrellin A and hypomycin B are compared on a time scale of several hundreds of picoseconds. No deuterium isotope effect is observed for hypomycin B. This result is discussed in the light of the previous assignment of the primary photoprocess in hypocrellin A to hydrogen atom transfer.

Organic cofactors participated more frequently than transition metals in redox reactions of primitive proteins.

Protein redox reactions are one of the most basic and important biochemical actions. As amino acids are weak redox mediators, most protein redox functions are undertaken by protein cofactors, which include organic ligands and transition metal ions. Since both kinds of redox cofactors were available in the pre-protein RNA world, it is challenging to explore which one was more involved in redox processes of primitive proteins? In this paper, using an examination of the redox cofactor usage of putative ancient proteins, we infer that organic ligands participated more frequently than transition metals in redox reactions of primitive proteins, at least as protein cofactors. This is further supported by the relative abundance of amino acids in the primordial world. Supplementary material for this article can be found on the BioEssays website.

Gene Expression Analysis of Four Radiation-resistant Bacteria

To investigate the general radiation-resistant mechanisms of bacteria, bioinformatic method was employed to predict highly expressed genes for four radiation-resistant bacteria, i.e. Deinococcus geothermalis (D. geo), Deinococcus radiodurans (D. rad), Kineococcus radiotolerans (K. rad) and Rubrobacter xylanophilus (R. xyl). It is revealed that most of the three reference gene sets, i.e. ribosomal proteins, transcription factors and major chaperones, are generally highly expressed in the four bacteria. Recombinase A (recA), a key enzyme in recombinational repair, is predicted to be highly or marginally highly expressed in the four bacteria. However, most proteins associated with other repair systems show low expression levels. Some genes participating in ‘information storage and processing,’ ‘cellular processes and signaling’ and ‘metabolism’ are among the top twenty predicted highly expressed (PHX) genes in the four genomes. Many antioxidant enzymes and proteases are commonly highly expressed in the four bacteria, indicating that these enzymes play important roles in resisting irradiation. Finally, a number of ‘hypothetical genes’ are among the top twenty PHX genes in each genome, some of them might contribute vitally to resist irradiation. Some of the prediction results are supported by experimental evidence. All the above information not only helps to understand the radiation-resistant mechanisms but also provides clues for identifying new radiation-resistant genes from these bacteria.

How does gene expression level contribute to thermophilic adaptation of prokaryotes? An exploration based on predictors

By analyzing the predicted gene expression levels of 33 prokaryotes with living temperature span from <10 degrees C to >100 degrees C, a universal positive correlation was found between the percentage of predicted highly expressed genes and the organisms optimal growth temperature. A physical interpretation of the correlation revealed that highly expressed genes are statistically more thermostable than lowly expressed genes. These findings show the possibility of the significant contribution of gene expression level to the prokaryotic thermal adaptation and provide evidence for the translational selection pressure on the thermostability of natural proteins during evolution.

DCCP and DICP: Construction and Analyses of Databases for Copper- and Iron-Chelating Proteins

Copper and iron play important roles in a variety of biological processes, especially when being chelated with proteins. The proteins involved in the metal binding, transporting and metabolism have aroused much interest. To facilitate the study on this topic, we constructed two databases (DCCP and DICP) containing the known copper- and iron-chelating proteins, which are freely available from the website http://sdbi.sdut.edu.cn/en. Users can conveniently search and browse all of the entries in the databases. Based on the two databases, bioinformatic analyses were performed, which provided some novel insights into metalloproteins.