Computational insights into monkeypox clade II protein interactions with human proteins HACE1 TTBK2 and KLHL3 in reproductive tissues

Because of its increased tissue tropism and potential sexual transmission, the Clade II Monkeypox virus (MPXV) has caused serious concerns globally. Although MPXV’s host entry and immune evasion mechanisms have been studied, little is known about how it can exploit host reproductive tissues, proteins, and associated pathways. We investigated whether MPXV Clade II proteins exhibit putative structural resemblance to host reproductive proteins with the potential to dysregulate tissue-specific signalling pathways. Differentially expressed genes (DEG) identified in infected host datasets were intersected with reproductive tissue-enriched proteins derived from the Human Protein Atlas (HPA). Comparative analysis revealed potential targets that could be altered in reproductive tissues during MPXV infection, especially via sexual transmission. To evaluate host–pathogen interactions based on structural resemblance, the host and viral protein sequences of identified DEGs were aligned, followed by structural modelling with AlphaFold2, molecular docking, and molecular dynamics simulation. Key viral proteins- OPG037 and OPG187- showed high structural similarity to host HACE1 and TTBK2, respectively, generating the hypothesis that OPG037 may bind RAC1, a crucial GTPase controlling cellular migration. Similarly, the Kelch and BTB-BACK domains of KLHL3 showed putative structural similarity to the Kelch and BTB-BACK domains of MPXV Kelch-like protein. It raises the hypothesis that it may compete with the host Kelch domain of KLHL3 to bind WNK3 and the BTB-BACK domain of KLHL3 to bind CUL3. These findings suggest MPXV Clade II proteins exhibit putative structural resemblance with potential functional implications requiring validation. This study elucidates docking-based host–pathogen interactions to generate hypotheses on molecular mechanisms behind viral pathogenesis in sexual organs. This provides insights essential for mitigating the spread of emerging MPXV variants with enhanced potential for human-to-human sexual transmission.