scholarly journals Deciphering Structural Alterations Associated with Activity Reductions of Genetic Polymorphisms in Cytochrome P450 2A6 Using Molecular Dynamics Simulations

2021 ◽  
Vol 22 (18) ◽  
pp. 10119
Author(s):  
Koichi Kato ◽  
Tomoki Nakayoshi ◽  
Rika Nokura ◽  
Hiroki Hosono ◽  
Masahiro Hiratsuka ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Cytochrome P450 ◽  
Molecular Dynamics Simulations ◽  
Genetic Polymorphisms ◽  
Structural Changes ◽  
Three Dimensional ◽  
Smoking Behavior ◽  
Enzymatic Activities ◽  
Access Channel ◽  
Dynamics Simulations

Cytochrome P450 (CYP) 2A6 is a monooxygenase involved in the metabolism of various endogenous and exogenous chemicals, such as nicotine and therapeutic drugs. The genetic polymorphisms in CYP2A6 are a cause of individual variation in smoking behavior and drug toxicities. The enzymatic activities of the allelic variants of CYP2A6 were analyzed in previous studies. However, the three-dimensional structures of the mutants were not investigated, and the mechanisms underlying activity reduction remain unknown. In this study, to investigate the structural changes involved in the reduction in enzymatic activities, we performed molecular dynamics simulations for ten allelic mutants of CYP2A6. For the calculated wild type structure, no significant structural changes were observed in comparison with the experimental structure. On the other hand, the mutations affected the interaction with heme, substrates, and the redox partner. In CYP2A6.44, a structural change in the substrate access channel was also observed. Those structural effects could explain the alteration of enzymatic activity caused by the mutations. The results of simulations provide useful information regarding the relationship between genotype and phenotype.

scholarly journals Structural variability and concerted motions of the T cell receptor – CD3 complex

2021 ◽  
Author(s):  
Prithvi R. Pandey ◽  
Bartosz Różycki ◽  
Reinhard Lipowsky ◽  
Thomas R. Weikl
Keyword(s):  
Molecular Dynamics ◽  
T Cell ◽  
Molecular Dynamics Simulations ◽  
T Cell Receptor ◽  
Tilt Angle ◽  
Structural Changes ◽  
Cell Receptor ◽  
Transmembrane Helices ◽  
Dynamics Simulations ◽  
Tcr Activation

AbstractWe investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) – CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined by Dong et al. (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15° to 55°. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR – CD3 complex, in particular in the EC interactions of the Cβ FG loop of the TCR, as well as in the orientation of transmembrane helices. The concerted motions of the membrane-embedded TCR – CD3 complex revealed in our simulations provide atomistic insights for force-based models of TCR activation, which involve such structural changes in response to tilt-inducing forces on antigen-bound TCRs.

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