MOTIVATION: Molecular dynamics (MD) simulations provide critical insights into biomolecular processes but they generate complex high-dimensional data that are often difficult to interpret directly. Dimensionality reduction methods like principal component analysis, time-lagged independent component analysis, and self-organizing maps (SOMs) have helped in extracting essential information on functional dynamics. However, there is a growing need for a user-friendly and flexible framework for SOM-based analyses of MD simulations. Such a framework should offer adaptable workflows, customizable options, and direct integration with a widely adopted analysis software. RESULTS: We designed and developed SOMMD, an R package to streamline MD analysis workflows. SOMMD facilitates the interpretation of atomistic trajectories through SOMs, providing tools for each stage of the workflow, from importing a wide range of MD trajectories data types to generating enhanced visualizations. The package also includes three example projects that demonstrate how SOM can be applied in real-world scenarios, including cluster analysis, pathways mapping and transition networks reconstruction. AVAILABILITY AND IMPLEMENTATION: SOMMD is available on CRAN (https://CRAN.R-project.org/package=SOMMD) and on GitHub (https://github.com/alepandini/SOMMD).

Hypoxia inducible factors (HIFs) are transcription factors belonging to the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) protein family with a role in sensing oxygen levels in the cell. Under hypoxia, the HIF-α degradation pathway is blocked and dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT) makes HIF-α transcriptionally active. Due to the common hypoxic environment of tumors, inhibition of this mechanism by destabilization of HIF-α:ARNT dimerization has been proposed as a promising therapeutic strategy. Following the discovery of a druggable cavity within the PAS-B domain of HIF-2α, research efforts have been directed to identify artificial ligands that can impair heterodimerization. Although the crystallographic structures of the HIF-2α:ARNT complex have elucidated the dimer architecture and the 0X3-inhibitor placement within the HIF-2α PAS-B, unveiling the inhibition mechanism requires investigation of how ligand-induced perturbations could dynamically propagate through the structure and affect dimerization. To this end, we compared evolutionary features, intrinsic dynamics and energetic properties of the dimerization interfaces of HIF-2α:ARNT in both the apo and holo forms. Residue conservation analysis highlighted inter-domain connecting elements that have a role in dimerization. Analysis of domain contributions to the dimerization energy demonstrated the importance of bHLH and PAS-A of both partners and of HIF-2α PAS-B domain in dimer stabilization. Among quaternary structure oscillations revealed by Molecular Dynamics simulations, the hinge-bending motion of the ARNT PAS-B domain around the flexible PAS-A/PAS-B linker supports a general model for ARNT dimerization in different heterodimers. Comparison of the HIF-2α:ARNT dynamics in the apo and 0X3-bound forms indicated a model of inhibition where the HIF-2α-PAS-B interfaces are destabilised as a result of water-bridged ligand-protein interactions and these local effects allosterically propagate to perturb the correlated motions of the domains and inter-domain communication. These findings will guide the design of improved inhibitors to contrast cell survival in tumor masses.