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Computational Model of Phosphatidylinositol Protonation in Membranes
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Resumo(s)
Phosphatidylinositols (PIPs) are ubiquitous signaling molecules with distinct biological roles and metabolisms that are tightly controlled. Their structural properties are primarily defined by the characteristics of their polar head group. At physiological pH, this polar head group is highly negatively charged, enabling it to form strong electrostatic interactions. The global protonation state of PIPs significantly influences their binding affinities and specificity for certain protein domains, as well as their interactions with other lipids (including PIPs themselves) and divalent cations. Molecular-level studies of PIPs have been conducted using computational methods that introduce significant approximations to their preferred protonation states. Therefore, in this work, we developed a computational model with fewer approximations that accurately describes the protonation dynamics of PIPs. To achieve our goals, we used our in-house constant-pH molecular dynamics (CpHMD) code to simulate the inositol ring, employing the CHARMM force field. CpHMD simulations were first performed for four inositol rings (Ins(1,2)P2, Ins(1,2,3)P3, Ins(1,2,6)P3, and Ins(1,4,5)P3), whose results are in agreement with the experimental NMR data, validating the model’s predictive ability. Three membrane systems (PI4P, PI(4,5)P2, and PI(3,4,5)P3) in a POPC lipid bilayer were tested under two conditions: infinite dilution (ID) and 9% molar fraction of PIPs. PIPs/POPC CpHMD simulations allowed us to quantify the impact of the lipid bilayer and concentration, fully capturing the effect of the environment. This is a crucial step towards understanding how pH affects PIPs’ interactions and further comprehending the role of protonation in their binding affinities, which are essential for their diverse functions.
Descrição
Tese de Mestrado, Bioquímica e Biomedicina, 2025, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Phosphatidylinositols pH Protonation Membrane Constant-pH Molecular Dynamics