Impact of K16A and K28A mutation on the structure and dynamics of amyloid-β₄₂ peptide in Alzheimer’s disease: key insights from molecular dynamics simulations

Abstract

The aggregation of amyloid-β₄₂ (Aβ₄₂) peptide into toxic oligomers and fibrils is a key step in the Alzheimer disease pathogenesis. The recent studies highlighted that lysine residues (K16 and K28) play a critical role in the Aβ₄₂ self-assembly and are the target of entities like molecular tweezer, CLR01. The studies reveal that lysine to alanine mutation significantly affect Aβ oligomerization, toxicity and aggregation process. However, the molecular mechanism behind reduced Aβ toxicity on K16A and K28A mutation remain elusive. In this regard, molecular dynamics (MD) simulations were performed in the present study to get insights into the effect of K16A and K28A mutation in Aβ₄₂ self-assembly. The MD simulations highlighted that K16A and K28A mutation in the aggregation-prone region, i.e., central hydrophobic core (KLVFF, 16–20) and bend region (D23–K28), cause major structural changes in the Aβ₄₂ monomer. The secondary structure analysis highlight that modulation of aggregation in K16A and K28A is linked to the increase in the overall helix content and a concomitant decrease in the β–sheet content of Aβ₄₂ monomer. The short-range tertiary contacts between central hydrophobic core and C-terminal region were relatively reduced in K16A and K28A as compare to wild type (wt) Aβ₄₂. The mechanistic insights from the study will be beneficial for the design and development of novel inhibitors that will bind and block the interactions, mediated by lysine residues specifically, critical for the Aβ₄₂ self-assembly in Alzheimer disease.

The molecular mechanism behind modulation of amyloid-β₄₂ (Aβ₄₂) self-assembly on K16A and K28A mutation has been investigated using molecular dynamics (MD) simulations. MD simulations reveal that reduced aggregation in K16A and K28A is linked to the increase in the overall helix content and a concomitant decrease in the β–sheet content, particularly at the C–terminal region, of Aβ₄₂.

Communicated by Ramaswamy H. Sarma

Keywords:

• Alzheimer’s disease
• amyloid-β peptide
• conformational transition
• molecular dynamics
• mutation

Acknowledgments

The authors acknowledge C-DAC, Pune for providing the C-DAC's supercomputing resources (PARAM Yuva-II) for the computational facilities. The authors acknowledge School of Chemistry & Biochemistry, Thapar Institute of Engineering & Technology, Patiala, Punjab and Department of Chemistry, Sri Guru Granth Sahib World University, Fatehgarh Sahib, Punjab, India for providing the research facilities.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

Bhupesh Goyal (Sanction No: SB/FT/CS-013/2014) and Deepti Goyal (Sanction No: YSS/2015/000320) gratefully acknowledges Science and Engineering Research Board (SERB), Department of Science & Technology, Government of India for the award of SERB Start-Up Research Grant (Young Scientists).