On electrostatic interactions of adenosine triphosphate-insulin-degrading enzyme revealed by quantum mechanics/molecular mechanics and molecular dynamics

The insulin-degrading enzyme(IDE)plays a significant role in the degradation of the amyloid beta(Aβ),a peptide found in the brain regions of the patients with early Alzheimer’s disease.Adenosine triphosphate(ATP)allosterically regulates the Aβ-degrading activity of IDE.The present study investigates the electrostatic interactions between ATP-IDE at the allosteric site of IDE,including thermostabilities/flexibilities of IDE residues,which have not yet been explored systematically.This study applies the quantum mechanics/molecular mechanics(QM/MM)to the proposed computational model for exploring electrostatic interactions between ATP and IDE.Molecular dynamic(MD)simulations are performed at different temperatures for identifying flexible and thermostable residues of IDE.The proposed computational model predicts QM/MM energy-minimised structures providing the IDE residues(Lys530 and Asp385)with high binding affinities.Considering root mean square fluctuation values during the MD simulations at 300.00 K including heat-shock temperatures(321.15 K and 315.15 K)indicates that Lys530 and Asp385 are also the thermostable residues of IDE,whereas Ser576 and Lys858 have high flexibilities with compromised thermostabilities.The present study sheds light on the phenomenon of biological recognition and interactions at the ATP-binding domain,which may have important implications for pharmacological drug design.The proposed computational model may facilitate the development of allosteric IDE activators/inhibitors,which mimic ATP interactions.

Alleviating the unwanted effects of oxidative stress on Aβclearance:a review of related concepts and strategies for the development of computational modelling

Treatment for Alzheimer’s disease(AD)can be more effective in the early stages.Although we do not completely understand the aetiology of the early stages of AD,potential pathological factors(amyloid beta[Aβ]and tau)and other co-factors have been identified as causes of AD,which may indicate some of the mechanism at work in the early stages of AD.Today,one of the primary techniques used to help delay or prevent AD in the early stages involves alleviating the unwanted effects of oxidative stress on Aβclearance.4-Hydroxynonenal(HNE),a product of lipid peroxidation caused by oxidative stress,plays a key role in the adduction of the degrading proteases.This HNE employs a mechanism which decreases catalytic activity.This process ultimately impairs Aβclearance.The degradation of HNE-modified proteins helps to alleviate the unwanted effects of oxidative stress.Having a clear understanding of the mechanisms associated with the degradation of the HNE-modified proteins is essential for the development of strategies and for alleviating the unwanted effects of oxidative stress.The strategies which could be employed to decrease the effects of oxidative stress include enhancing antioxidant activity,as well as the use of nanozymes and/or specific inhibitors.One area which shows promise in reducing oxidative stress is protein design.However,more research is needed to improve the effectiveness and accuracy of this technique.This paper discusses the interplay of potential pathological factors and AD.In particular,it focuses on the effect of oxidative stress on the expression of the Aβ-degrading proteases through adduction of the degrading proteases caused by HNE.The paper also elucidates other strategies that can be used to alleviate the unwanted effects of oxidative stress on Aβclearance.To improve the effectiveness and accuracy of protein design,we explain the application of quantum mechanical/molecular mechanical approach.