Investigation The Physical Mechanism Of Amyloid Fibrosis Using Molecular Dynamics Simulation

At present, several intractable amyloid diseases are serious threats to human health, which including type-II diabetes mellitus (T2DM), Alzheimer’s disease and Parkinson’s disease, etc. More and more research results show that amyloid fibrils formed by amyloid protein/peptide (such as amyloid-β peptide, a-synuclein, and human Islet Amyloid Polypeptide (hIAPP)) are linked to such diseases. The insoluble amyloid deposits leading to various diseases are widely distributed in organelles and neurons, although they are formed by different kinds of protein when denatured, the deposits have similar fibers, and they share a common property that is nucleation-dependent fibril growth. At present, most research direction is mainly concentrated in two aspects:first, to explore the nucleation mechanism of amyloid fibrils and the diversity of assembly; second, how to prevent/inhibit the accumulation of amyloid fibrils. The amyloid fibrils usually presents a variety of different morphologies observed by experiment, which indicating various assembly behaviors. The soluble intermediate oligomers and the precursor fiber oligomers proved to be the most cytotoxic forms to cells. The existing time of critical nucleus in elongation stage is shorter, and it is difficult to capture in experiment. In this article, the main research objects are the segments of hIAPP2o-29 protofibrillar oligomers, the full length hIAPP 1-37 protofibrillar oligomers and amyloid β-protein (Aβ1-42) dimers.Basing on the classical physics theory, molecular dynamics simulation can simulate the microscopic movement of individual atoms changing over time in biological system, then study protein’s structure and the related properties combined with statistical mechanics principle. Now we can use a kind of software, such as GROMACS, AMBER and so on, to simulate the phenomenon that is hard to get in experiment. It can explain the experimental phenomena from the atomic level and pave the way for better understanding of the molecular basis of diseases, and then design new drugs.The accuracy of MD depends on the force field. The current pre-calculated and static force fields, for example, OPLS and AMBER, often fail to consider the polarization, which will bring great errors to simulation results. For this bottleneck in dynamics, our group developed polarized protein-specific charges, hereinafter referred to as PPC. In this paper, we first apply PPC to the dynamics simulation of amyloid fibers, and investigate the effect of polarization on the stability and cooperative nucleation of the segment of hIAPP20-29 and the full length hIAPP1-37 protofibrillar oligomers. Simulation results show that the electrostatic polarization effect can effectively maintain the dynamic stability of hIAPP oligomers. In addition, using a method considering the effect of polarization to calculate the electrostatic interaction (EI) energy between adjacent β-chain, we found that the EI energy between the two adjacent monomers (1 and 2) increase very fast in the first three oligomers. If we increase monomers from both sides, the increation of EI energy can multiply, which provides strong evidence for the cooperative assembly of the hIAPP oligomers, and is also consistent with the experimental observations of the slow nucleation and fast growth.The increased accumulation of extracellular hIAPP in diabetic patients showed that pH change may promote the formation of amyloid protein. In order to further explore the influence of pH on hIAPP fibrillogenesis, we performed several molecular dynamics simulations in explicit solvent model to study the conformational properties of five hIAPP protofibrillar oligomers respectively under pH 5.5 and pH 7.4. The simulation results are consistent with the experimental results:these oligomers are flexible under acidic pH. Besides, our simulation results reveal that the acidic pH mainly influence the structural stability by destroying the hydrogen-bonding network of the local structure around residue His18. This is mainly due to the electrostatic repulsion between charged interchain His18 residues at pH 5.5. This suggests that the local interactions nearby His 18 on the adjacent β-monomer can lead to structural transformation, which gives guidance to the experimental results:the rate of hIAPP fibril formation and the morphologies of the fibrillar structures strongly depend on pH.An obvious hallmark of Alzheimer’s disease is that there exist amyloid deposits or plaques made of the amyloid β-protein (Aβ) in the brain. Recently many studies showed that small molecules or short peptide can inhibit the formation of deposits effectively, thus reducing cytotoxicity. However, the mechanism underlying the inhibitory effects of these molecules is poorly understood. We explored the interactions between Aβ1-42 dimer and small molecule 1, 4-napthoquinon-2-yl-L-tryptophan (NQtrp) in the fifth chapter. Our results show that the NQtrp has a preference for charged and hydrophobic residues(including ARG LYS GLU HIS MET TYR LEU). Then NQtrp was decomposed into six functional group: CO, CO, COO-,NH, indole and NQ. From the results of matrix of binding propensity between NQtrp functional groups and Aβ1-42, we can see that the binding propensity from high to low is in the order:NQ>CO’>CO>COO->indole>NH. The aromatic groups on NQ played an important role in interacting with Aβ1-42 dimer.