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Protein Hot-Spots (HS) are experimentally determined amino acids, key to small ligand binding and tend to be structural landmarks on protein-protein interactions. As such, they were extensively approached by structure-based Machine Learning (ML) prediction methods. However, the availability of a much larger array of protein sequences in comparison to determined tree-dimensional structures indicates that a sequence-based HS predictor has the potential to be more useful for the scientific community. Herein, we present SPOTONE, a new ML predictor able to accurately classify protein HS via sequence-only features. This algorithm shows accuracy, AUROC, precision, recall and F1-score of 0.82, 0.83, 0.91, 0.82 and 0.85, respectively, on an independent testing set. The algorithm is deployed within a free-to-use webserver at http://moreiralab.com/resources/spotone, only requiring the user to submit a FASTA file with one or more protein sequences.

Membrane proteins are essential vessels for cell communication both with other cells and noncellular structures. They modulate environment responses and mediate a myriad of biological processes. Dimerization and multimerization processes have been shown to further increase the already high specificity of these processes. Due to their central role in various cell and organism functions, these multimers are often associated with health conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), and diabetes, among others.Understanding the membrane protein dimers' interface takes advantage of the specificity of the structure, for which we must pinpoint the most relevant interfacial residues, since they are extremely likely to be crucial for complex formation. Here, we describe step by step our own in silico protocol to characterize these residues, making use of known experimental structures. We detail the computational pipeline from data acquisition and pre-processing to feature extraction. A molecular dynamics simulation protocol to further study membrane dimer proteins and their interfaces is also illustrated.