Evaluation for interaction energy between glutamine and various chemical compounds for developing the virtual screening system using DFT quantum chemical calculations

摘要

Polyglutamine (polyQ) diseases, including Huntington's disease (HD), are caused by expansion of polyQ-encoding repeats within otherwise unrelated gene products. The quantum chemical calculations revealed the following. The effective molecular interaction is between glutamine (Gln) and Gln (Gln+Gln), between Gln and Congo red (Gln+Congo red), between Gln and trehalose (Gln+trehalose), between Gln and glucose (Gln+glucose), between Gln and mannose (Gln+mannose) and between Gln and melbiose (Gln+melbiose). These obtained interaction strengths are good agreement with the experimental results of inhibitor and alleviator for polyQ aggregation. Based on our results, we propose the inhibition mechanism of Congo red, and the alleviation mechanism of trehalose. Our proposed mechanism can explain the inhibition effect by Congo red as an inhibitor of polyglutamine-induced protein aggregation and the alleviation effect by trehalose as an alleviator of that aggregation. We assume that the interaction energy of Gln+Gln is a trigger for the polyQ aggregation and discuss that an aggregation mechanism whose heat generated by the intermolecular Gln+Gln formation causes the pathogeny of polyQ disease. We developed the virtual screening system that searched for ideal inhibitor that can have polyQ aggregation blocking effect as like Congo red and crossed the blood brain barrier in addition by using our estimation method. The virtual screening system can be constructed by building this system into the massively parallel computer like IBM BlueGene/L supercomputer.