Integrating chemistry, biophysics and physiology in the evolution of mammalian Myoglobins
This work describes an integration between chemistry, molecular biophysics, physiology, sequence evolution and bioinformatics to better understand the evolution of mammalian myoglobins (Mb) in terms of their primary biochemical function (i.e., O2 binding) and their thermodynamic stability (i.e., fol...
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| Format: | Book |
| Language: | English |
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DTU Chemical Engineering
2013
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| Online Access: | https://orbit.dtu.dk/en/publications/21117d6f-e45e-4e2e-ba92-f3cb6e514c60 https://backend.orbit.dtu.dk/ws/files/58423796/Pouria%20Dasmeh-PhD%20Thesis-DTU%20Chemistry-April2013.pdf |
| Summary: | This work describes an integration between chemistry, molecular biophysics, physiology, sequence evolution and bioinformatics to better understand the evolution of mammalian myoglobins (Mb) in terms of their primary biochemical function (i.e., O2 binding) and their thermodynamic stability (i.e., folding free energy). First, we merge a large set of previously reported thermochemical data for Mb mutants with a physiological model of O2 delivery in the skeletal muscle cells to quantify the functional proficiency of Mb mutants under various physiological conditions. We find that O2-storage and –transport are distinct functions which depend on O2 partial pressure and conclude that conserved residues in wild type (WT) Mb were fixated under a selection pressure of low ܲைమ . Second, we present an integrated model of convective O2-transport and O2-affinity of mutant Mb to quantify the impacts of mutations in Mb on the aerobic dive limits (ADL) of Weddell seals (Leptonychotes weddellii). We show that wild-type Mb traits are only superior under specific physiological conditions that critically prolong the ADL, action radius, and fitness of the seals. Third, we deal with the observation of higher folding stabilities (i.e., ΔGfolding) of cetacean Mbs compared to their terrestrial counterparts. 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 (i.e., ΔΔGfolding), we observe accelerated evolution in cetaceans and identify seven positively selected sites in Mb. We show that these sites contribute to Mb stabilization by favoring hydrophobic folding, structural integrity, and intra-helical hydrogen bonds. Finally, we ask a fundamental question that how a general protein phenotype such as folding stability, that was shown as an example to be positively selected in cetacean Mbs in the iv third part of this thesis, affects the rate of protein evolution. Using a model that combines ... |
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