The Initial Theoretical Study Of Biological-Physical-Chemical Behaviours On Complex Systems

Biological system is a kind of typical complex system because of its large structure, apparent multiple levels and certain regularity. In this work, two complex systems are studied:artificial helices and transthyretin (TTR).1.artificial helicesHelical structures exist in many nature systems, such as DNA, proteins, collagens, and so on. Inspired by various structures and functions of biological systems, chemists dedicate themselves to synthesize artificial macromolecules and try to wind them into multiple-strand helices in experiments.The polymer of 7-amino-8-fluoro-2-quinoline carboxylic acid (abbreviated as QFn, n denotes polymerization degree, where n equal to 4 or 8) can form artificial helices that do not exist in nature. The crystal structures of the quadruplex of QF4 and the duplex of QF8 (abbreviated as QP₄ and DP₈, respectively) have been unveiled by some researchers recently. In this paper, QP₄ and DP₈ were built based on their crystal structures. Though the quadruplex of QF8 and the duplex of QF4 (abbreviated as QP₈ and DP₄, respectively) were not observed in experiments, they were built using molecular modeling tools. The molecular dynamics (MD) method was used to study the stabilities and assembly mechanisms of these helices at different temperatures. In MD simulations, the disassembled QP₄ was observed above 480 K. The results indicate that these oligoamide helices showed slippage of strands to some extent and that double-helical oligoamides act as a basic block in the slippage during the formation of the quadruple-helical structure. DP₄ and QP₄ showed dynamical features with helix-handedness inversion and following slippage of strands at higher temperatures. In addition, theÏ€-Ï€conjugations between the different chains are supposed to be responsible for the stability of the helices.2.transthyretin (TTR)Transthyretin (TTR) is mainly produced in liver, choroids plexus and retina. It plays a significant role in human plasma, which is the backup carrier of the thyroxine (T4) and the only one of vitamin A via retinol binding protein (RBP). In some cases, TTR tetramer can dissociated into monomeric intermediates, which is further aggregated into amyloid protofibrils. The amyloidogenic TTR can deposited preferentially in peripheral nerve giving rise to familial amyloid polyneuropathy (FAP), or in the heart leading to familial amyloid cardiomyopathy (FAC), and amyloid fibers formed by WT-TTR induce occurrence of senile systemic amyloidosis (SSA). The small molecules can bind selectively with TTR central channel, stabilizing the tetramer against dissociation to prevent TTR from amyloid. In this study, we used 3D-QSAR and docking methods to study the inhibitory activities of 95 bisaryloxime ethers analogues (BSE). PHASE module of Schrodinger suit was been used to elucidate pharmacophore and build QSAR model. The pharmacophore AHRR hypothesis was generated using 38 molecules in the training set (R2=0.9145) and tested using 57 molecules in BSE (Q2=0.5638) as well as another external 9 similar molecules (Q2=0.7712, Pearson-R=0.8649), indicating good predictive ability. The docking study was also carried out to dock the inhibitors in the binding pocket of TTR in order to reveal the interactions between the inhibitors and TTR. X-Score score function was adopted to re-evaluate the interactions. The results obtained from the above studies showed the good predictive ability of PHASE for BSE inhibitors. The method adopted in this study is scientific, effective and give a good explaination of inhibitory ability of BSE. The aim of study is to design inhibitor which has good inhibitory activity, good selectivity and low toxicity.