Hong-Fang Ji

The Role of Electrostatic Interaction in Triggering the Unraveling of Stable Helix 1 in Normal Prion Protein. A Molecular Dynamics Simulation Investigation

Abstract The conversion of normal prion protein (PrPC) into scrapie isoform (PrPSc) is a key event in the pathogenesis of prion diseases. However, the conversion mechanism has given rise to much controversy. For instance, there is much debate on the behavior of helix 1 (H1) in the conversion. A series of experiments demonstrated that H1 in isolated state was very stable under a variety of conditions. But, other experiments indicated that helices 2 and 3 rather than H1 were retained in PrPSc. In this paper, molecular dynamics (MD) simulation is employed to investigate the dynamic behavior of H1. It is revealed that although the helix 1 of Human PrPC (HuPrPC) is very stable in the isolated state, it becomes unstable when incorporated into native HuPrPC, which likely results from the long-range electrostatic interaction between Asp147 and Arg208 located in the helices 1 and 3, respectively. This explanation is supported by experimental evaluation and MD simulation on D147N mutant of HuPrPC that the mutant becomes a little more stable than the wild type HuPrPC. This finding not only help to reconcile the existing debate on the role of helix 1 in the PrPC→PrPSc transition, but also reveals a possible mechanism for triggering the PrPC→PrPSc conversion.

Protein Architecture Chronology Deduced From Structures of Amino Acid Synthases

Abstract Inferring the protein architecture chronology is one of central topics in origin of life study and has been given much attention. Based on an amino acid evolutionary model that late amino acids were bio-synthesized prior to early counterparts, we addressed the issue by examining the structures of amino acid synthases. Despite the limited structural information on amino acid synthases, our deduction revealed that α/β was the oldest protein class, which is in good agreement with the prior fold-usage-based conclusion.

Bioinformatic Identification of the Most Ancient Copper Protein Architecture

Abstract Since copper ions participate in many cellular processes and are implicated in pathogenesis of many diseases, copper proteins have important biological significance. Thus, it is of interest to explore their origins, especially to address the following question: which is the most ancient architecture of copper proteins? In this paper, through analyzing the architectural features of copper proteins, we find that the fold-domain relationship of these proteins follows a power law, which can be explained by preferential attachment principle and implicates that the architecture of the most ancient copper proteins belonged to Cupredoxin-like (b.6) fold. According to the chronology of protein folds, this architecture originated rather late, which can be understood in terms of the low abundance of reducing amino acids (e.g., His, Cys and/or Met) in the primordial world, because these amino acids are required by copper proteins to bind copper ions.

Rat's Trick to Escape Alzheimer's Disease

Abstract Amyloid β (Aβ) peptides fibril formation and deposition is considered to be the principal pathological hallmark of Alzheimers disease (AD). However, it remains obscure why AD is precluded by rat/mouse despite the high sequence identity (97%) of rat/mouse Aβ to its human homologue. Based on the recently proposed redox chemistry-based pathogenic model of neurodegenerative diseases, we hypothesize that the lack of key residues of rat/mouse Aβ compared with the human counterpart may account for why rat/mouse is free of AD. At the same time, we propose a new possible redox chemistry-based pathogenic model of AD based on the experimental observations of certain residues in triggering Aβ aggregation. Moreover, it is also interesting to note that non-mammalian Xenopus Aβ contains all the redox chemistry-related key residues and whether it implies that Xenopus Aβ possesses high amyloidogenic potency remains to be determined by further experimental study.