@article {535,
	title = {Localized structural frustration for evaluating the impact of sequence variants.},
	journal = {Nucleic Acids Res},
	volume = {44},
	year = {2016},
	month = {2016 12 01},
	pages = {10062-10073},
	abstract = {<p>Population-scale sequencing is increasingly uncovering large numbers of rare single-nucleotide variants (SNVs) in coding regions of the genome. The rarity of these variants makes it challenging to evaluate their deleteriousness with conventional phenotype-genotype associations. Protein structures provide a way of addressing this challenge. Previous efforts have focused on globally quantifying the impact of SNVs on protein stability. However, local perturbations may severely impact protein functionality without strongly disrupting global stability (e.g. in relation to catalysis or allostery). Here, we describe a workflow in which localized frustration, quantifying unfavorable local interactions, is employed as a metric to investigate such effects. Using this workflow on the Protein Databank, we find that frustration produces many immediately intuitive results: for instance, disease-related SNVs create stronger changes in localized frustration than non-disease related variants, and rare SNVs tend to disrupt local interactions to a larger extent than common variants. Less obviously, we observe that somatic SNVs associated with oncogenes and tumor suppressor genes (TSGs) induce very different changes in frustration. In particular, those associated with TSGs change the frustration more in the core than the surface (by introducing loss-of-function events), whereas those associated with oncogenes manifest the opposite pattern, creating gain-of-function events.</p>},
	keywords = {Computational Biology, Databases, Protein, Evolution, Molecular, Genes, Tumor Suppressor, Genetic Variation, Humans, Neoplasms, Oncogenes, Polymorphism, Single Nucleotide, Proteins, Workflow},
	issn = {1362-4962},
	doi = {10.1093/nar/gkw927},
	author = {Kumar, Sushant and Clarke, Declan and Gerstein, Mark}
}
@article {104,
	title = {Reads meet rotamers: structural biology in the age of deep sequencing.},
	journal = {Curr Opin Struct Biol},
	volume = {35},
	year = {2015},
	month = {2015 Dec},
	pages = {125-34},
	abstract = {<p>Structure has traditionally been interrelated with sequence, usually in the framework of comparing sequences across species sharing a common fold. However, the nature of information within the sequence and structure databases is evolving, changing the type of comparisons possible. In particular, we now have a vast amount of personal genome sequences from human populations and a greater fraction of new structures contain interacting proteins within large complexes. Consequently, we have to recast our conception of sequence conservation and its relation to structure-for example, focusing more on selection within the human population. Moreover, within structural biology there is less emphasis on the discovery of novel folds and more on relating structures to networks of protein interactions. We cover this changing mindset here. </p>},
	keywords = {High-Throughput Nucleotide Sequencing, Humans, Isomerism, Mutation, Proteins},
	issn = {1879-033X},
	doi = {10.1016/j.sbi.2015.11.003},
	author = {Sethi, Anurag and Clarke, Declan and Chen, Jieming and Kumar, Sushant and Galeev, Timur R and Regan, Lynne and Gerstein, Mark}
}
