scholarly journals Investigations of the Underlying Mechanisms of HIF-1α and CITED2 Binding to TAZ1

2019 ◽  
Author(s):  
Wen-Ting Chu ◽  
Xiakun Chu ◽  
Jin Wang
Keyword(s):  
Energy Surface ◽  
Feedback Regulation ◽  
Creb Binding Protein ◽  
Free Energy Surface ◽  
Contact Map ◽  
Negative Feedback Regulation ◽  
Dominant Position ◽  
Apparent Affinity ◽  
Thermodynamics And Kinetics ◽  
Underlying Mechanisms

AbstractThe TAZ1 domain of CREB binding protein is crucial for transcriptional regulation and recognizes multiple targets. The interactions between TAZ1 and its specific targets are related to the cellular hypoxic negative feedback regulation. Previous experiments reported that one of the TAZ1 targets CITED2 is an efficient competitor of another target HIF-1α. Here by developing the structure-based models of TAZ1 complexes we have uncovered the underlying mechanisms of the competitions between HIF-1α and CITED2 binding to TAZ1. Our results are consistent with the experimental hypothesis on the competition mechanisms and the apparent affinity. In addition, the simulations prove the dominant position of forming TAZ1-CITED2 complex in both thermodynamics and kinetics. For thermodynamics, TAZ1-CITED2 is the lowest basin located on the free energy surface of binding in the ternary system. For kinetics, the results suggest that CITED2 binds to TAZ1 faster than HIF-1α. Besides, the analysis of contact map and ϕ values in this study will be helpful for further experiments on TAZ1 systems.

scholarly journals Investigations of the underlying mechanisms of HIF-1α and CITED2 binding to TAZ1

2020 ◽  
Vol 117 (11) ◽  
pp. 5595-5603 ◽  
Author(s):  
Wen-Ting Chu ◽  
Xiakun Chu ◽  
Jin Wang
Keyword(s):  
Energy Surface ◽  
Experimental Studies ◽  
Feedback Regulation ◽  
Disordered Proteins ◽  
Creb Binding Protein ◽  
Free Energy Surface ◽  
Contact Map ◽  
Negative Feedback Regulation ◽  
Dominant Position ◽  
Underlying Mechanisms

The TAZ1 domain of CREB binding protein is crucial for transcriptional regulation and recognizes multiple targets. The interactions between TAZ1 and its specific targets are related to the cellular hypoxic negative feedback regulation. Previous experiments reported that one of the TAZ1 targets, CITED2, is an efficient competitor of another target, HIF-1α. Here, by developing the structure-based models of TAZ1 complexes, we have uncovered the underlying mechanisms of the competitions between the two intrinsic disordered proteins (IDPs) HIF-1α and CITED2 binding to TAZ1. Our results support the experimental hypothesis on the competition mechanisms and the apparent affinity. Furthermore, the simulations locate the dominant position of forming TAZ1–CITED2 complex in both thermodynamics and kinetics. For thermodynamics, TAZ1–CITED2 is the lowest basin located on the free energy surface of binding in the ternary system. For kinetics, the results suggest that CITED2 binds to TAZ1 faster than HIF-1α. In addition, the analysis of contact map and Φ values is important for guiding further experimental studies to understand the biomolecular functions of IDPs.

scholarly journals High-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology

2021 ◽  
Author(s):  
Jay F Storz
Keyword(s):  
High Altitude ◽  
Hypoxia Inducible Factor ◽  
Feedback Regulation ◽  
Genomic Analyses ◽  
Manipulative Experiments ◽  
Altitude Adaptation ◽  
Mechanisms Of Adaptation ◽  
Physiological Pathways ◽  
Underlying Mechanisms ◽  
Integrated Genomics

AbstractPopulation genomic analyses of high-altitude humans and other vertebrates have identified numerous candidate genes for hypoxia adaptation, and the physiological pathways implicated by such analyses suggest testable hypotheses about underlying mechanisms. Studies of highland natives that integrate genomic data with experimental measures of physiological performance capacities and subordinate traits are revealing associations between genotypes (e.g., hypoxia-inducible factor gene variants) and hypoxia-responsive phenotypes. The subsequent search for causal mechanisms is complicated by the fact that observed genotypic associations with hypoxia-induced phenotypes may reflect second-order consequences of selection-mediated changes in other (unmeasured) traits that are coupled with the focal trait via feedback regulation. Manipulative experiments to decipher circuits of feedback control and patterns of phenotypic integration can help identify causal relationships that underlie observed genotype–phenotype associations. Such experiments are critical for correct inferences about phenotypic targets of selection and mechanisms of adaptation.

scholarly journals Exploration of Free Energy Surface and Thermal Effects on Relative Population and Infrared Spectrum of the Be6B11− Fluxional Cluster

Materials ◽  
2020 ◽  
Vol 14 (1) ◽  
pp. 112
Author(s):  
Carlos Emiliano Buelna-Garcia ◽  
José Luis Cabellos ◽  
Jesus Manuel Quiroz-Castillo ◽  
Gerardo Martinez-Guajardo ◽  
Cesar Castillo-Quevedo ◽  
...  
Keyword(s):  
Free Energy ◽  
Infrared Spectrum ◽  
Infrared Spectra ◽  
Thermal Effects ◽  
Global Minimum ◽  
Energy Surface ◽  
Weighted Sums ◽  
Free Energy Surface ◽  
Temperature Dependent ◽  
Relative Population

The starting point to understanding cluster properties is the putative global minimum and all the nearby local energy minima; however, locating them is computationally expensive and difficult. The relative populations and spectroscopic properties that are a function of temperature can be approximately computed by employing statistical thermodynamics. Here, we investigate entropy-driven isomers distribution on Be6B11− clusters and the effect of temperature on their infrared spectroscopy and relative populations. We identify the vibration modes possessed by the cluster that significantly contribute to the zero-point energy. A couple of steps are considered for computing the temperature-dependent relative population: First, using a genetic algorithm coupled to density functional theory, we performed an extensive and systematic exploration of the potential/free energy surface of Be6B11− clusters to locate the putative global minimum and elucidate the low-energy structures. Second, the relative populations’ temperature effects are determined by considering the thermodynamic properties and Boltzmann factors. The temperature-dependent relative populations show that the entropies and temperature are essential for determining the global minimum. We compute the temperature-dependent total infrared spectra employing the Boltzmann factor weighted sums of each isomer’s infrared spectrum and find that at finite temperature, the total infrared spectrum is composed of an admixture of infrared spectra that corresponds to the spectra of the lowest-energy structure and its isomers located at higher energies. The methodology and results describe the thermal effects in the relative population and the infrared spectra.

Sign in / Sign up

Export Citation Format

Share Document