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Hydrophobic interactions have long been established as essential for stabilizing structured proteins as well as drivers of aggregation, but the impact of hydrophobicity on the functional significance of sequence variants has rarely been considered in a genomewide context. Here we test the role of hydrophobicity on functional impact across 70,000 disease- and non–disease-associated single-nucleotide polymorphisms (SNPs), using enrichment of disease association as an indicator of functionality. We find that functional impact is uncorrelated with hydrophobicity of the SNP itself and only weakly correlated with the average local hydrophobicity, but is strongly correlated with both the size and minimum hydrophobicity of the contiguously hydrophobic sequence (or “blob”) that contains the SNP. Disease association is found to vary by more than sixfold as a function of contiguous hydrophobicity parameters, suggesting utility as a prior for identifying causal variation. We further find signatures of differential selective constraint on hydrophobic blobs and that SNPs splitting a long hydrophobic blob or joining two short hydrophobic blobs are particularly likely to be disease associated. Trends are preserved for both aggregating and nonaggregating proteins, indicating that the role of contiguous hydrophobicity extends well beyond aggregation risk. [ABSTRACT FROM AUTHOR]

The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) in precursor brain-derived neurotrophic factor (BDNF) is one of the earliest SNPs to be associated with neuropsychiatric disorders, and the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica-exchange molecular dynamics (MD) simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence. The simulations were able to correctly reproduce the location of both local and non-local secondary structure changes due to the Val66Met mutation, when compared with NMR spectroscopy. We find that the change in local structure is mediated via entropic and sequence specific effects. We developed a hierarchical sequence-based framework for analysis and conceptualization, which first identifies "blobs" of 4-15 residues representing local globular regions or linkers. We use this framework within a novel test for enrichment of higher-order (tertiary) structure in disordered proteins; the size and shape of each blob is extracted from MD simulation of the real protein (RP), and used to parameterize a self-avoiding heterogenous polymer (SAHP). The SAHP version of the BDNF prodomain suggested a protein segmented into three regions, with a central long, highly disordered polyampholyte linker separating two globular regions. This effective segmentation was also observed in full simulations of the RP, but the Val66Met substitution significantly increased interactions across the linker, as well as the number of participating residues. The Val66Met substitution replaces β-bridging between V66 and V94 (on either side of the linker) with specific side-chain interactions between M66 and M95. The protein backbone in the vicinity of M95 is then free to form β-bridges with residues 31-41 near the N-terminus, which condenses the protein. A significant role for Met/Met interactions is consistent with previously-observed non-local effects of the Val66Met SNP, as well as established interactions between the Met66 sequence and a Met-rich receptor that initiates neuronal growth cone retraction. Intrinsically disordered proteins are proteins that have no well-defined structure in at least one functional form. Mutations in one amino acid may still affect their function significantly, especially in subtle ways with cumulative adverse effects on health. Here we report on molecular dynamics simulations of a protein that is critical for neuronal health throughout adulthood (brain-derived neurotrophic factor). We investigate the effects of a mutation carried by 30% of human population, which has been widely studied for its association with aging-related and stress-related disorders, reduced volume of the hippocampus, and variations in episodic memory. We identify a molecular mechanism in which the mutation may change the global conformations of the protein and its ability to bind to receptors. [ABSTRACT FROM AUTHOR]