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Modeling effects of human single nucleotide polymorphisms on protein-protein interactions.

ABSTRACT: A large set of three-dimensional structures of 264 protein-protein complexes with known nonsynonymous single nucleotide polymorphisms (nsSNPs) at the interface was built using homology-based methods. The nsSNPs were mapped on the proteins' structures and their effect on the binding energy was investigated with CHARMM force field and continuum electrostatic calculations. Two sets of nsSNPs were studied: disease annotated Online Mendelian Inheritance in Man (OMIM) and nonannotated (non-OMIM). It was demonstrated that OMIM nsSNPs tend to destabilize the electrostatic component of the binding energy, in contrast with the effect of non-OMIM nsSNPs. In addition, it was shown that the change of the binding energy upon amino acid substitutions is not related to the conservation of the net charge, hydrophobicity, or hydrogen bond network at the interface. The results indicate that, generally, the effect of nsSNPs on protein-protein interactions cannot be predicted from amino acids' physico-chemical properties alone, since in many cases a substitution of a particular residue with another amino acid having completely different polarity or hydrophobicity had little effect on the binding energy. Analysis of sequence conservation showed that nsSNP at highly conserved positions resulted in a large variance of the binding energy changes. In contrast, amino acid substitutions corresponding to nsSNPs at nonconserved positions, on average, were not found to have a large effect on binding affinity. pKa calculations were performed and showed that amino acid substitutions could change the wild-type proton uptake/release and thus resulting in different pH-dependence of the binding energy.

SUBMITTER: Teng S

PROVIDER: S-EPMC2717281 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Modeling effects of human single nucleotide polymorphisms on protein-protein interactions.

Teng Shaolei S Madej Thomas T Panchenko Anna A Alexov Emil E

Biophysical journal 20090301 6

A large set of three-dimensional structures of 264 protein-protein complexes with known nonsynonymous single nucleotide polymorphisms (nsSNPs) at the interface was built using homology-based methods. The nsSNPs were mapped on the proteins' structures and their effect on the binding energy was investigated with CHARMM force field and continuum electrostatic calculations. Two sets of nsSNPs were studied: disease annotated Online Mendelian Inheritance in Man (OMIM) and nonannotated (non-OMIM). It w ...[more]

PMID: 19289044

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Project description:BK Ca2+-activated K+ channels are important regulators of membrane excitability. Multiple regulatory mechanisms tailor BK current properties across tissues, such as alternative splicing, posttranslational modifications, and auxiliary subunits. Another potential mechanism for modulating BK channel activity is genetic variation due to single nucleotide polymorphisms (SNPs). The gene encoding the human BK α subunit, KCNMA1, contains hundreds of SNPs. However, the variation in BK channel activity due to SNPs is not well studied. Here, we screened the effects of four SNPs (A138V, C495G, N599D, and R800W) on BK currents in HEK293T cells, selected based on predicted protein pathogenicity or disease linkage. We found that the SNPs C495G and R800W had the largest effects on BK currents, affecting the conductance-voltage relationship across multiple Ca2+ conditions in the context of two BK channel splice variants. In symmetrical K+, C495G shifted the V1/2 to more hyperpolarized potentials (by -15 to -20 mV) and accelerated activation, indicating C495G confers some gain-of-function properties. R800W shifted the V1/2 to more depolarized potentials (+15 to +35 mV) and slowed activation, conferring loss-of-function properties. Moreover, the C495G and R800W effects on current properties were found to persist with posttranslational modifications. In contrast, A138V and N599D had smaller and more variable effects on current properties. Neither application of alkaline phosphatase to patches, which results in increased BK channel activity attributed to channel dephosphorylation, nor bidirectional redox modulations completely abrogated SNP effects on BK currents. Lastly, in physiological K+, C495G increased the amplitude of action potential (AP)-evoked BK currents, while R800W had a more limited effect. However, the introduction of R800W in parallel with the epilepsy-linked mutation D434G (D434G/R800W) decreased the amplitude of AP-evoked BK currents compared with D434G alone. These results suggest that in a physiological context, C495G could increase BK activation, while the effects of the loss-of-function SNP R800W could oppose the gain-of-function effects of an epilepsy-linked mutation. Together, these results implicate naturally occurring human genetic variation as a potential modifier of BK channel activity across a variety of conditions.

Dataset Information

Modeling effects of human single nucleotide polymorphisms on protein-protein interactions.

Publications

Modeling effects of human single nucleotide polymorphisms on protein-protein interactions.

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