# Insights into Membrane Damage by \(\alpha\)-Helical and \(\beta\)-Sheet Peptides
## 1 Introduction  
Disruption of lipid membranes by amphipathic peptides and their aggregates contributes to cytotoxic effects in amyloid diseases such as Alzheimer's disease by inducing neuronal damage, resulting in cognitive and motor decline [1, 2, 3, 4]. This phenomenon also plays a key role in host defense, as many organisms express amphipathic peptides that target bacterial membranes, while selectively sparing eukaryotic cells [5, 6, 7]. This selectivity has motivated efforts to develop amphipathic peptides as therapeutic agents for bacterial infections, and to target and destroy cancer cells [8, 9, 10, 11]. These empirical efforts have provided only limited insight into the detailed interactions and pathways that cause membranedisruption. Greater mechanistic understanding will lead to the discovery of principles to guide the design of novel therapeutic agents [12; 13; 14; 15]. Insights into these principles can be obtained via high-throughput analyses of peptide databases, and all-atom simulations combined with validating biophysical/biochemical experiments. In 2025, nearly 3500 antimicrobial peptides (AMP) have been reported in the literature [16; 17]. Most of them exhibit a net positive charge (88%), with only a small fraction being neutral (6%) or negative (6%) [18]. These observations likely reflect the necessity of charge complementarity for positive AMPs to target negatively charged components of bacterial membranes [19]. In contrast, amyloid peptides often only display small and often variable net charges, which facilitates aggregation and self-assembly. Moreover, for amyloids and AMPs, approximately 40-60% of the residues are nonpolar [18]. Hydrophobic amino acids drive the aggregation of amyloid peptides and are critical to account for membrane adsorption [20]. The distribution of these residues along the peptide sequence determines the conformation of peptides at the water-lipid interface. AMPs show a preference for adopting \(\alpha\)-helical (16%) compared to \(\beta\)-sheet (2%) structures [16], which is often encoded in sequences containing variations of the (XXYY)\({}_{n}\) template [21; 22; 23], where X and Y correspond to hydrophobic and polar/charged residues, respectively, and n varies between 2 and 4. In contrast, amyloids self-assemble into \(\beta\)-sheet structures that can be encoded in various sequence patterns, including those where nonpolar and polar/charged residues alternate [24; 25; 26; 27], for example, (XY\({}_{1}\)XY\({}_{2}\))\({}_{n}\). The (XXYY)\({}_{n}\) and (XY\({}_{1}\)XY\({}_{2}\))\({}_{n}\) sequence templates can adopt secondary structures that are amphiphilic, with one of their faces being mostly nonpolar and the other polar. At the water-lipid interface, the former is buried inside the acyl-tail of lipids, whereas the latter is exposed to the solvent and lipid head groups [20]. Some peptides with these sequence patterns tend to damage lipid bilayers [21; 22; 23; 24; 28; 29; 30], which accounts for the increase in the rate of solvent permeation and disrupts ion homeostasis leading to cell death. This damage can manifest via a self-assembly process in which peptides form _pore-like structures_, accumulate in one of the membrane's leaflets via a _carpet-like mechanism_, or dissolve the lipid content of the membrane in a _detergent-like manner_[31; 32; 33; 34]. Several properties of the amino acid sequence can significantly affect the membrane-damaging nature of AMPs and amyloids. This includes the length of the peptides, which, in some cases, have to be long enough to span the two leaflets of the bilayer [35; 36; 37]. Increasing the amphiphilicity of peptides enhances secondary structure stability, which can increase the rate of water permeation [38; 39; 40; 15; 41]. In the case of \(\alpha\)-helices, this includes taking into account that a complete turn contains 3.6 amino acids, and not 4 as assumed in the (XXYY)\({}_{n}\) pattern [39].