Mutual information analysis of mutation, nonlinearity, and triple interactions in proteins

Erman, Burak

doi:10.1002/prot.26415

Cited by 5 publications

(2 citation statements)

References 50 publications

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“…Therefore, recourse to simplified expressions based on the correlation matrix becomes inevitable. An alternative method of expressing mutual information in terms of Hermite series was proposed recently, 60 which requires the evaluation of higher moments of the covariance matrix.…”

Section: Methodsmentioning

confidence: 99%

Synergy and anti‐cooperativity in allostery: Molecular dynamics study of WT and oncogenic KRAS‐RGL1

Hacisuleyman,

Erman

2023

Proteins

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This study focuses on investigating the effects of an oncogenic mutation (G12V) on the stability and interactions within the KRAS‐RGL1 protein complex. The KRAS‐RGL1 complex is of particular interest due to its relevance to KRAS‐associated cancers and the potential for developing targeted drugs against the KRAS system. The stability of the complex and the allosteric effects of specific residues are examined to understand their roles as modulators of complex stability and function. Using molecular dynamics simulations, we calculate the mutual information, MI, between two neighboring residues at the interface of the KRAS‐RGL1 complex, and employ the concept of interaction information, II, to measure the contribution of a third residue to the interaction between interface residue pairs. Negative II indicates synergy, where the presence of the third residue strengthens the interaction, while positive II suggests anti‐cooperativity. Our findings reveal that MI serves as a dominant factor in determining the results, with the G12V mutation increasing the MI between interface residues, indicating enhanced correlations due to the formation of a more compact structure in the complex. Interestingly, although II plays a role in understanding three‐body interactions and the impact of distant residues, it is not significant enough to outweigh the influence of MI in determining the overall stability of the complex. Nevertheless, II may nonetheless be a relevant factor to consider in future drug design efforts. This study provides valuable insights into the mechanisms of complex stability and function, highlighting the significance of three‐body interactions and the impact of distant residues on the binding stability of the complex. Additionally, our findings demonstrate that constraining the fluctuations of a third residue consistently increases the stability of the G12V variant, making it challenging to weaken complex formation of the mutated species through allosteric manipulation. The novel perspective offered by this approach on protein dynamics, function, and allostery has potential implications for understanding and targeting other protein complexes involved in vital cellular processes. The results contribute to our understanding of the effects of oncogenic mutations on protein–protein interactions and provide a foundation for future therapeutic interventions in the context of KRAS‐associated cancers and beyond.

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Section: Methodsmentioning

confidence: 99%

Synergy and anti‐cooperativity in allostery: Molecular dynamics study of WT and oncogenic KRAS‐RGL1

Hacisuleyman,

Erman

2023

Proteins

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“…The undeniable asset of multivariate quantification of dependency has recently been demonstrated by the work of Erman (2023) . Here, the author analyzed the molecular dynamics of a structural domain found in a broad variety of signaling proteins.…”

Section: Introductionmentioning

confidence: 99%

BannMI deciphers potential n-to-1 information transduction in signaling pathways to unravel message of intrinsic apoptosis

Schmidt,

Sers,

Klein

2023

Bioinformatics Advances

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Cell fate decisions, such as apoptosis or proliferation, are communicated via signaling pathways. The pathways are heavily intertwined and often consist of sequential interaction of proteins (kinases). Information integration takes place on the protein level via n-to-1 interactions. A state-of-the-art procedure to quantify information flow (edges) between signaling proteins (nodes) is network inference. However, edge weight calculation typically refers to 1-to-1 interactions only and relies on mean protein phosphorylation levels instead of single cell distributions. Information theoretic measures such as the mutual information (MI) have the potential to overcome these shortcomings but are still rarely used. This work proposes a Bayesian nearest neighbor (NN)-based MI estimator (BannMI) to quantify n-to-1 kinase dependency in signaling pathways. BannMI outperforms the state-of-the-art MI estimator on protein-like data in terms of mean squared error and Pearson correlation. Using BannMI, we analyse apoptotic signaling in phosphoproteomic cancerous and non-cancerous breast cell line data. Our work provides evidence for cooperative signaling of several kinases in programmed cell death and identifies a potential key role of the mitogen-activated protein (MAP) kinase p38.

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Lernen aus Protein‐Engineering durch Dekonvolution von Multi‐Mutationalen Enzymvarianten**

Hollmann,

Sanchis,

Reetz

2024

Angewandte Chemie

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This review analyzes a development in biochemistry, enzymology and biotechnology that originally came as a surprise. As part of directed evolution of stereoselective enzymes in organic chemistry, the concept of partial or complete deconvolution of selective multi‐mutational variants was established and refined during the past 15 years. Early deconvolution experiments of stereoselective variants led to the finding that mutations can interact cooperatively or antagonistically with one another, not just additively. Later, this phenomenon was shown to be general. Molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) computations were performed in order to shed light on the origin of non‐additivity at all stages of an evolutionary upward climb. Data of complete deconvolution can be used to construct unique multi‐dimensional rugged fitness pathway landscapes, which provide more mechanistic insight than traditional fitness landscapes. Along a related line, biochemists have long tested the result of introducing two point mutations in an enzyme for mechanistic reasons, followed by a comparison of the respective double mutant in so‐called double mutant cycles, which originally showed only additive effects, but more recently also uncovered cooperative and antagonistic non‐additive effects.

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Mutual information analysis of mutation, nonlinearity, and triple interactions in proteins

Cited by 5 publications

References 50 publications

Synergy and anti‐cooperativity in allostery: Molecular dynamics study of WT and oncogenic KRAS‐RGL1

Synergy and anti‐cooperativity in allostery: Molecular dynamics study of WT and oncogenic KRAS‐RGL1

BannMI deciphers potential n-to-1 information transduction in signaling pathways to unravel message of intrinsic apoptosis

Lernen aus Protein‐Engineering durch Dekonvolution von Multi‐Mutationalen Enzymvarianten**

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