Functional elucidation of hypothetical proteins for their indispensable roles toward drug designing targets from Helicobacter pylori strain HPAG1

Helicobacter pylori is a flagellated and slow growing gram-negative bacterium that persistently infects about half of the entire world population. In present study, we examined the proteome of H. pylori strain HPAG1 for identification of key uncharacterized proteins toward their novel regulatory functions. The complete proteome of this strain consists of 1539 proteins, out of which 520 proteins are annotated as hypothetical. Based on the functional motifs in their primary sequences, we were able to classify 254 of these hypothetical proteins into 6 functional categories. Further, KEGG database was used to find the roles of these hypothetical proteins in several pathways and structural prediction was done by homology modeling methods. Thirty-three of these hypothetical proteins were found to have strong association in various pathways including signaling and defense mechanisms. We noted that 27 of these proteins are specific to H. pylori and can be selected for drug designing targets, based on their virulence and regulatory role. We were able to successfully model the 3D structures of three of these proteins: YP_626977.1, YP_626786.1, and YP_628146.1. The stability of these proteins was also validated using molecular dynamics simulations, and their possible role in the regulation of different pathways was explained. These novel annotations may contribute to the understanding of disease mechanism at molecular level and provide novel potential targets for designing new drugs against H. pylori strain HPAG1.

幽门螺杆菌（Helicobacter pylori）是一种带鞭毛、生长缓慢的革兰氏阴性菌，可持续感染全球约半数人口。本研究针对幽门螺杆菌HPAG1菌株的蛋白质组展开分析，旨在鉴定关键未表征蛋白并探索其新型调控功能。该菌株的完整蛋白质组包含1539种蛋白，其中520种被注释为假想蛋白。基于其一级序列中的功能基序，本研究将其中254种假想蛋白划分为6个功能类别。此外，本研究借助京都基因与基因组百科全书（KEGG）数据库分析了这些假想蛋白在多条通路中的作用，并通过同源建模法完成了结构预测。研究发现，其中33种假想蛋白在信号传导、防御机制等多种通路中存在显著关联。本研究观察到，其中27种蛋白为幽门螺杆菌所特有，结合其毒力与调控功能，可作为药物研发的潜在靶点。本研究成功解析了其中3种蛋白的三维结构：YP_626977.1、YP_626786.1及YP_628146.1。此外，本研究通过分子动力学模拟验证了这些蛋白的稳定性，并阐释了它们在不同通路调控中的潜在作用。这些全新的蛋白注释有助于从分子层面阐明幽门螺杆菌的致病机制，并为针对HPAG1菌株的抗幽门螺杆菌新药研发提供新型潜在靶点。