AbstractProteins fold from chains of amino acids, forming secondary structures, α-helices and β-strands, that, at least for globular proteins, subsequently fold into a three-dimensional structure. A large-scale analysis of high-resolution protein structures suggests that amino acid pairs constitute another layer of ordered structure, more local than these conventionally defined secondary structures. We develop a cross-peptide-bond Ramachandran plot that captures the conformational preferences

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... the amino acid pairs and show that the effect of a particular mutation on the stability of a protein depends in a predictable manner on the adjacent amino acid context.One-Sentence SummaryLarge-scale protein backbone analysis reveals amino acid pair conformational preferences and predicts how sequence context affects mutant stability.