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Cell shape, cytoplasmic viscosity, and membrane stability are the main determinants of erythrocyte deformability, but it remains unknown how these properties affect the merozoite invasiveness. This study aimed to investigate computationally (i) the role of erythrocyte morphology and merozoite-induced erythrocyte membrane damage in merozoite invasion and (ii) the suitability of mechanical markers of merozoite-induced erythrocyte membrane damage for screening of invasion-blocking antimalarial drugs. Finite element models were developed to represent a human erythrocyte and a spherocyte, their invasion by a malaria merozoite, and erythrocyte compression and nanoindentation as mechanical assays for membrane damage. Smoothed particle hydrodynamics represented the erythrocyte cytoplasm, and merozoite-induced erythrocyte membrane damage was implemented with a constitutive model. The invasiveness of the merozoite decreases with increased erythrocyte sphericity associated with genetic disorders such as hereditary spherocytosis. The invasiveness is larger when membrane damage is induced in the erythrocyte at an early invasion stage than throughout the invasion process. The minimum force required for a malaria merozoite to invade a human erythrocyte was predicted to be 11 pN. The findings on the invasion mechanics can guide future studies into the invasiveness of the merozoite. The nanoindentation simulations point to the potential of nanoindentation to determine erythrocyte membrane damage for screening novel invasion-blocking antimalarial drugs.<\/jats:p>","DOI":"10.1007\/s10237-026-02062-w","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T14:29:41Z","timestamp":1776436181000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In silico analysis of the invasion mechanics and invasiveness of the Plasmodium falciparum merozoite"],"prefix":"10.1007","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1021-9308","authenticated-orcid":false,"given":"Chimwemwe","family":"Msosa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0320-811X","authenticated-orcid":false,"given":"Tamer","family":"Abdalrahman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1504-3842","authenticated-orcid":false,"given":"Thomas","family":"Franz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"issue":"4","key":"2062_CR1","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1007\/s10867-017-9463-6","volume":"43","author":"T Abdalrahman","year":"2017","unstructured":"Abdalrahman T, Franz T (2017) Analytical modeling of the mechanics of early invasion of a merozoite into a human erythrocyte. 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