Association Rate Constants of Ras-Effector Interactions Are Evolutionarily Conserved

Kiel, Christina; Aydin, Dorothee; Serrano, Luís

doi:10.1371/journal.pcbi.1000245

Cited by 16 publications

(10 citation statements)

References 62 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, all mutations were studied using the FoldX force field [28]–[30] to investigate whether the sites under selection in some way contribute to the stability phenotype of the Mbs (See Methods section for details).…”

Section: Resultsmentioning

confidence: 99%

Positively Selected Sites in Cetacean Myoglobins Contribute to Protein Stability

et al. 2013

View full text Add to dashboard Cite

Since divergence ∼50 Ma ago from their terrestrial ancestors, cetaceans underwent a series of adaptations such as a ∼10–20 fold increase in myoglobin (Mb) concentration in skeletal muscle, critical for increasing oxygen storage capacity and prolonging dive time. Whereas the O2-binding affinity of Mbs is not significantly different among mammals (with typical oxygenation constants of ∼0.8–1.2 µM−1), folding stabilities of cetacean Mbs are ∼2–4 kcal/mol higher than for terrestrial Mbs. Using ancestral sequence reconstruction, maximum likelihood and Bayesian tests to describe the evolution of cetacean Mbs, and experimentally calibrated computation of stability effects of mutations, we observe accelerated evolution in cetaceans and identify seven positively selected sites in Mb. Overall, these sites contribute to Mb stabilization with a conditional probability of 0.8. We observe a correlation between Mb folding stability and protein abundance, suggesting that a selection pressure for stability acts proportionally to higher expression. We also identify a major divergence event leading to the common ancestor of whales, during which major stabilization occurred. Most of the positively selected sites that occur later act against other destabilizing mutations to maintain stability across the clade, except for the shallow divers, where late stability relaxation occurs, probably due to the shorter aerobic dive limits of these species. The three main positively selected sites 66, 5, and 35 undergo changes that favor hydrophobic folding, structural integrity, and intra-helical hydrogen bonds.

show abstract

Section: Resultsmentioning

confidence: 99%

Positively Selected Sites in Cetacean Myoglobins Contribute to Protein Stability

et al. 2013

View full text Add to dashboard Cite

show abstract

“…For in silico experiments, a generic mouse-specific computational model has been generated based on the human-specific ModCell™ model ( 12 , 13 ), leveraging the conservation and homologies existing between human and mouse genes, proteins, network structure, individual signaling relevant protein–protein interactions, and post-translational events ( 40 – 45 ). The mouse-specific computational model is then “personalized” with multi-layered omics data (e.g., exome, transcriptome, quantitative proteome, and phosphoproteome data), from individual tumor and control mouse tissues at different disease stages.…”

Section: Models Of Models: the Use Of Preclinical Models For Optimizimentioning

confidence: 99%

Models of Models: A Translational Route for Cancer Treatment and Drug Development

et al. 2017

View full text Add to dashboard Cite

Every patient and every disease is different. Each patient therefore requires a personalized treatment approach. For technical reasons, a personalized approach is feasible for treatment strategies such as surgery, but not for drug-based therapy or drug development. The development of individual mechanistic models of the disease process in every patient offers the possibility of attaining truly personalized drug-based therapy and prevention. The concept of virtual clinical trials and the integrated use of in silico, in vitro, and in vivo models in preclinical development could lead to significant gains in efficiency and order of magnitude increases in the cost effectiveness of drug development and approval. We have developed mechanistic computational models of large-scale cellular signal transduction networks for prediction of drug effects and functional responses, based on patient-specific multi-level omics profiles. However, a major barrier to the use of such models in a clinical and developmental context is the reliability of predictions. Here we detail how the approach of using “models of models” has the potential to impact cancer treatment and drug development. We describe the iterative refinement process that leverages the flexibility of experimental systems to generate highly dimensional data, which can be used to train and validate computational model parameters and improve model predictions. In this way, highly optimized computational models with robust predictive capacity can be generated. Such models open up a number of opportunities for cancer drug treatment and development, from enhancing the design of experimental studies, reducing costs, and improving animal welfare, to increasing the translational value of results generated.

show abstract

“…Here the protein structural details come in handy (Aloy & Russell, 2006). Apart from providing the details of how to model a reaction qualitatively, computational methods can also help us with estimation of quantitative parameters of an interaction, such as association rate constants (Kiel, Aydin, & Serrano, 2008). If the affinity constant is known for an interacting homologous protein pair then a range of affinity constants can be estimated using structural information and programs like FoldX (Beltrao et al, 2007; Guerois, Nielsen, & Serrano, 2002; J.…”

Section: The Way Forward: Multi-scale Modeling and Data Integrationmentioning

confidence: 99%

Modeling Intracellular Signaling Underlying Striatal Function in Health and Disease

Nair¹,

Gutierrez-Arenas²,

Eriksson³

et al. 2014

Progress in Molecular Biology and Translational Science

View full text Add to dashboard Cite

Striatum, which is the input nucleus of the basal ganglia, integrates cortical and thalamic glutamatergic inputs with dopaminergic afferents from the substantia nigra pars compacta. The combination of dopamine and glutamate strongly modulates molecular and cellular properties of striatal neurons and the strength of corticostriatal synapses. These actions are performed via intracellular signaling networks, containing several intertwined feedback loops. Understanding the role of dopamine and other neuromodulators requires the development of quantitative dynamical models for describing the intracellular signaling, in order to provide precise unambiguous descriptions and quantitative predictions. Building such models requires integration of data from multiple data sources containing information regarding the molecular interactions, the strength of these interactions, and the subcellular localization of the molecules. Due to the uncertainty, variability, and sparseness of these data, parameter estimation techniques are critical for inferring or constraining the unknown parameters, and sensitivity analysis evaluates which parameters are most critical for a given observed macroscopic behavior. Here, we briefly review the modeling approaches and tools that have been used to investigate biochemical signaling in the striatum, along with some of the models built around striatum. We also suggest a future direction for the development of such models from the, now becoming abundant, high-throughput data.

show abstract

Association Rate Constants of Ras-Effector Interactions Are Evolutionarily Conserved

Cited by 16 publications

References 62 publications

Positively Selected Sites in Cetacean Myoglobins Contribute to Protein Stability

Positively Selected Sites in Cetacean Myoglobins Contribute to Protein Stability

Models of Models: A Translational Route for Cancer Treatment and Drug Development

Modeling Intracellular Signaling Underlying Striatal Function in Health and Disease

Contact Info

Product

Resources

About