Integrative approaches for predicting protein network perturbations through machine learning and structural characterization.

Chromatin remodeling complexes, such as the Saccharomyces cerevisiae INO80 complex, exemplify how dynamic protein interaction networks govern cellular function through a balance of conserved structural modules and context-dependent functional partnerships, as revealed by integrative machine learning and structural mapping approaches. In this study, we explored the INO80 complex using machine learning to predict network changes caused by genetic deletions. Tree-based models outperformed linear approaches, highlighting non-linear relationships within the interaction network. Feature selection identified key INO80 components (e.g., Arp5, Arp8) and cross-compartment features from other remodeling complexes like SWR1 and NuA4, emphasizing shared functional pathways. Perturbation patterns aligned with biological modules, particularly those linked to telomere maintenance and aging, underscoring the functional coherence of these networks. Structural mapping revealed that not all interactions are predictable through proximity alone, particularly with Arp5 and Yta7. By combining structural insights with machine learning, we enhanced predictions of genetic perturbation effects, providing a template for analyzing cross-species homologs (e.g., human INO80) and their disease-associated variants. This integrative approach bridges the gap between static structural data and dynamic functional networks, offering a pathway to disentangle conserved mechanisms from context-dependent adaptations in chromatin biology. SIGNIFICANCE: By leveraging an innovative, integrative machine learning approach, we have successfully predicted and analyzed perturbations in the INO80 network with good accuracy and depth. Our novel combination of machine learning, perturbation analysis, and structural investigation approach has provided crucial insights into the complex's structure-function relationships, shedding new light on its pivotal roles in affected pathways such as telomere maintenance. Our findings not only enhance our understanding of the INO80 complex but also establish a powerful framework for future studies in chromatin biology and beyond. This work represents a step forward in our understanding of chromatin remodeling complexes and their diverse cellular functions, laying the groundwork for future studies that can further refine our computational approaches and experimental techniques in this field.