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"Infostery" analysis of short molecular dynamics simulations identifies highly sensitive residues and predicts deleterious mutations.

ABSTRACT: Characterizing a protein mutational landscape is a very challenging problem in Biology. Many disease-associated mutations do not seem to produce any effect on the global shape nor motions of the protein. Here, we use relatively short all-atom biomolecular simulations to predict mutational outcomes and we quantitatively assess the predictions on several hundreds of mutants. We perform simulations of the wild type and 175 mutants of PSD95's third PDZ domain in complex with its cognate ligand. By recording residue displacements correlations and interactions, we identify "communication pathways" and quantify them to predict the severity of the mutations. Moreover, we show that by exploiting simulations of the wild type, one can detect 80% of the positions highly sensitive to mutations with a precision of 89%. Importantly, our analysis describes the role of these positions in the inter-residue communication and dynamical architecture of the complex. We assess our approach on three different systems using data from deep mutational scanning experiments and high-throughput exome sequencing. We refer to our analysis as "infostery", from "info" - information - and "steric" - arrangement of residues in space. We provide a fully automated tool, COMMA2 ( www.lcqb.upmc.fr/COMMA2 ), that can be used to guide medicinal research by selecting important positions/mutations.

SUBMITTER: Karami Y

PROVIDER: S-EPMC6208415 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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"Infostery" analysis of short molecular dynamics simulations identifies highly sensitive residues and predicts deleterious mutations.

Karami Yasaman Y Bitard-Feildel Tristan T Laine Elodie E Carbone Alessandra A

Scientific reports 20181031 1

Characterizing a protein mutational landscape is a very challenging problem in Biology. Many disease-associated mutations do not seem to produce any effect on the global shape nor motions of the protein. Here, we use relatively short all-atom biomolecular simulations to predict mutational outcomes and we quantitatively assess the predictions on several hundreds of mutants. We perform simulations of the wild type and 175 mutants of PSD95's third PDZ domain in complex with its cognate ligand. By r ...[more]

PMID: 30382169

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Project description:Beneficial mutations drive adaptive evolution, yet their selective advantage does not ensure their fixation. Haldane's application of single-type branching process theory showed that genetic drift alone could cause the extinction of newly arising beneficial mutations with high probability. With linkage, deleterious mutations will affect the dynamics of beneficial mutations and might further increase their extinction probability. Here, we model the lineage dynamics of a newly arising beneficial mutation as a multitype branching process. Our approach accounts for the combined effects of drift and the stochastic accumulation of linked deleterious mutations, which we call lineage contamination We first study the lineage-contamination phenomenon in isolation, deriving dynamics and survival probabilities (the complement of extinction probabilities) of beneficial lineages. We find that survival probability is zero when [Formula: see text] where U is deleterious mutation rate and [Formula: see text] is the selective advantage of the beneficial mutation in question, and is otherwise depressed below classical predictions by a factor bounded from below by [Formula: see text] We then put the lineage contamination phenomenon into the context of an evolving population by incorporating the effects of background selection. We find that, under the combined effects of lineage contamination and background selection, ensemble survival probability is never zero but is depressed below classical predictions by a factor bounded from below by [Formula: see text] where [Formula: see text] is mean selective advantage of beneficial mutations, and [Formula: see text] This factor, and other bounds derived from it, are independent of the fitness effects of deleterious mutations. At high enough mutation rates, lineage contamination can depress fixation probabilities to values that approach zero. This fact suggests that high mutation rates can, perhaps paradoxically, (1) alleviate competition among beneficial mutations, or (2) potentially even shut down the adaptive process. We derive critical mutation rates above which these two events become likely.

Dataset Information

"Infostery" analysis of short molecular dynamics simulations identifies highly sensitive residues and predicts deleterious mutations.

Publications

"Infostery" analysis of short molecular dynamics simulations identifies highly sensitive residues and predicts deleterious mutations.

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