Exploring proteins and protein-ligand complexes through residue interaction networks.

Protein structures provide a wealth of information regarding biological functions and underlying mechanisms. The growing availability of high-quality structure predictions and extended molecular simulations has further expanded the potential to leverage these data in a myriad of different ways. Yet, an abundance of data can obscure important information, making it difficult to focus on biologically relevant features. Residue interaction networks (RINs) address this challenge by condensing structural data into subsets of well-defined noncovalent molecular interactions. In this Protocol, we explore how the RIN generator (RING) software can be used to gain biological insights by constructing detailed RINs for proteins and protein-ligand complexes. We provide a step-by-step guide to performing both single- and multi-state protein analyses using the RING web server and a stand-alone software package. In addition, we include a dedicated procedure for sequential multi-file analysis, which can be performed exclusively through the command-line interface. All potential inputs and outputs are explained in detail, along with strategies for downstream data processing. Designed for researchers in biology and related fields with minimal or no programming experience, the entire workflow can be completed in <45 min.