Document Type


Date of Award


Degree Name

Doctor of Philosophy in Applied Physics - (Ph.D.)



First Advisor

Cristiano L. Dias

Second Advisor

Tao Zhou

Third Advisor

Hao Chen

Fourth Advisor

Ian Gatley

Fifth Advisor

Andres Jerez

Sixth Advisor

Yong Ick Kim

Seventh Advisor

Mikko Haataja


The aggregation of amyloid proteins into fibrils is a hallmark of several diseases including Alzheimer’s (AD), Parkinson’s, and Type II diabetes. This aggregation process involves the formation of small size oligomers preceding the formation of insoluble fibrils. Recent studies have shown that these oligomers are more likely to be responsible for cell toxicity than fibrils. A possible mechanism of toxicity involves the interaction of oligomers with the cell membrane compromising its integrity. In particular, oligomers may form pore-like structures in the cell membrane affecting its permeability or they may induce lipid loss via a detergent-like effect. This dissertation aims to provide insights into these mechanisms of toxicity, which are poorly understood at the atomic level.

This dissertation kicks off with a molecular dynamics study of the interaction of individual amyloid-like peptides with lipid bilayers. It is found that both electrostatic and hydrophobic interactions contribute to peptide-membrane binding. In particular, the attraction of peptide to lipid bilayer is dominated by electrostatic interactions and hydrophobicity drives the burial of non-polar side chains into the interior of the bilayer. By changing the peptide sequence, positive net charges are shown to significantly strengthen peptide-membrane binding, whereas negative charges reduce their affinity drastically. Moreover, peptide-membrane binding can also be regulated by the position of positive residues in the peptide sequence which alters the exposure of positive side chains to the solvent. These results provide insights into the mechanism accounting for cell toxicity of amyloid proteins and the designing of antimicrobial peptides.

In this study, the first all-atom simulations are performed in which membrane-bound amphipathic peptides self-assemble into β-sheets that subsequently either form stable pores inside the bilayer or drag lipids out of the membrane surface. An analysis of these simulations shows that the acyl tails of lipids interact strongly with non-polar side chains of peptides deposited on the membrane. These strong interactions enable lipids to be dragged out of the bilayer by oligomeric structures accounting for detergent-like damage. Moreover, they disturb the orientation of lipid tails that are close to peptides. These distortions in lipid orientation are reduced close to pores contributing to stabilize these structures. These simulations also show that naturally twisted β-sheets are intermediate structures on pathway to poration. They enable water to partially penetrate the membrane triggering β-sheets to tilt and penetrate the membrane. The latter reduces interactions of solvent molecules with non-polar moieties of lipids. In addition, our simulations show that fibril-like structures produce little damage to lipid membranes as non-polar side chains in these structures are unavailable to interact with the acyl tail of lipids.



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