Atul, | bioRxiv Science

bioRxiv2024

An algorithm-based investigation reveals the differential dynamics of water inside protein cavity as a function of distance from its wall

Hydration forces exerted by water in the form of hydrogen bonding networks or electrostatic interactions play an essential role in protein structure and function. These interactions often govern chemical catalysis, ion transport, protein stability, and folding. While waters role as a biological solvent and on the protein surface is widely studied, its function inside protein cavities is often neglected due to the existing challenges in its detection using experimental and computational approaches. The importance of studying these special protein-water interactions is further underscored by the fact that water spatially confined within cavities exhibits deviations from bulk behavior, directly impacting processes occurring inside protein cavities. With these challenges in mind and building upon our method that accurately identifies the protein inner cavity surface (CICLOP), we have developed a tool that can accurately distinguish water occurring within cavities from the bulk solvent around the protein. Our tool can characterize the dynamic properties of water within protein cavities, such as diffusion, residence time, and rotational and orientational relaxation, using molecular dynamics (MD) simulation trajectories as input. We demonstrate the robustness of our tool on several cavity-containing proteins and describe its applicability in characterizing the biological function of water confined within the cavity of an archaeal group II chaperonin.

bioinformatics↗

bioRxiv2021

Plasmodium DDI1 is an essential chromatin-associated protein with a role in DNA-protein crosslink repair

DDI1 proteins are involved in a variety of cellular processes, including proteasomal degradation of specific proteins. All DDI1 proteins contain a ubiquitin-like (UBL) domain and a retroviral aspartyl protease (RVP) domain. Some DDI1 proteins also contain a ubiquitin-associated (UBA) domain. The three domains confer distinct activities to DDI1 proteins. The presence of RVP domain makes DDI1 a potential target of HIV protease inhibitors, which also block the development of malaria parasites. Hence, we investigated the DDI1 of malaria parasites to identify its roles during parasite development and potential as a therapeutic target. DDI1 proteins of Plasmodium and other Apicomplexan parasites share the UBL-RVP domain architecture, and some also contain the UBA domain. Plasmodium DDI1 is expressed across all the major life cycle stages and is important for parasite survival, as conditional depletion of DDI1 protein in the mouse malaria parasite Plasmodium berghei and the human malaria parasite Plasmodium falciparum compromised parasite development. Infection of mice with DDI1 knock-down P. berghei was self-limiting and protected the recovered mice from subsequent infection with homologous as well as heterologous parasites, indicating potential of DDI1 knock-down parasites as a whole organism vaccine. P. falciparum DDI1 (PfDDI1) is associated with chromatin and DNA-protein crosslinks. PfDDI1-depleted parasites accumulated DNA-protein crosslinks and showed enhanced susceptibility to DNA damaging chemicals, indicating a role of PfDDI1 in removal of DNA-protein crosslinks. Knock-down of PfDDI1 increased susceptibility to the retroviral protease inhibitor lopinavir and antimalarial artemisinin, which suggests that simultaneous inhibition of DDI1 could potentiate antimalarial activity of these drugs. As DDI1 knock-down parasites confer protective immunity and it could be a target of HIV protease inhibitors, Plasmodium DDI1 is a potential therapeutic target for malaria control.

cell biology↗