Our capacity to reliably predict protein structure from sequence is steadily improving due to the increased numbers and better targeting of protein structures being experimentally determined by structural genomics projects, along with the development of better modeling methodologies. Template-based (homology) modeling and de novo modeling methods are being combined to fill in remaining gaps in template coverage, and powerful automated structural modeling pipelines are being applied to large data sets of protein sequences. The improved quality of 3D models of proteins has led to their routine use in assessing the functional impact of nonsynonymous single nucleotide polymorphisms (nsSNPs) in specific protein systems, with the development of approaches that may be applied in a predictive fashion to nsSNPs emerging from next-generation sequencing projects. The challenges encountered in deriving functionally meaningful deductions from structural modeling can be quite different for proteins of different protein functional classes. The specific challenges to the assessment of the structural and functional impact of nsSNPs in globular proteins such as binding and regulatory proteins, structural proteins, and enzymes are discussed, as well as membrane transport proteins and ion channels. The mapping of reliable predictions of the structural and functional impact of SNPs, generated from automated modeling pipelines, on to protein-protein interaction networks will facilitate new approaches to understanding complex polygenic disorders and predisposition to disease.
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