Conformational Preference
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2021 ◽  
Alex van der Ham ◽  
Thomas Hansen ◽  
Hermen S. Overkleeft ◽  
Dmitri V. Filippov ◽  
Grégory F. Schneider ◽  

The physico-chemical properties of chiral propeller-shaped PAHs (propellerenes) are strongly dependent on their conformational behavior. A sound, physical model to understand why propellerenes exhibit a conformation preference for either a C2 or D3 conformation that moves beyond a phenomenological explanation is needed. We have therefore performed a computational study to rationalize the conformational preference of propellerenes. Using an activation strain analysis approach, we find that the conformational preference of propellerenes is ultimately determined by the flexibility of the wings. When wings are relatively flexible, as is the case for ortho-substituted propellerenes, a favorable contraction of the radial bonds connecting the core and the propellerene wings is possible, and the more distorted C2 conformation will be preferred. The more rigid wings of benzenoid propellerenes, on the other hand, cannot deform sufficiently, and will therefore always adopt a D3 conformation. Our approach represents a unique method to pinpoint the conformational preferences of propellerenes, and, in principle, any sterically congested molecule.

2021 ◽  
Vol 11 (1) ◽  
Gert-Jan Bekker ◽  
Ikuo Fukuda ◽  
Junichi Higo ◽  
Yoshifumi Fukunishi ◽  
Narutoshi Kamiya

AbstractWe have performed multicanonical molecular dynamics (McMD) based dynamic docking simulations to study and compare the binding mechanism between two medium-sized inhibitors (ABT-737 and WEHI-539) that bind to the cryptic site of Bcl-xL, by exhaustively sampling the conformational and configurational space. Cryptic sites are binding pockets that are transiently formed in the apo state or are induced upon ligand binding. Bcl-xL, a pro-survival protein involved in cancer progression, is known to have a cryptic site, whereby the shape of the pocket depends on which ligand is bound to it. Starting from the apo-structure, we have performed two independent McMD-based dynamic docking simulations for each ligand, and were able to obtain near-native complex structures in both cases. In addition, we have also studied their interactions along their respective binding pathways by using path sampling simulations, which showed that the ligands form stable binding configurations via predominantly hydrophobic interactions. Although the protein started from the apo state, both ligands modulated the pocket in different ways, shifting the conformational preference of the sub-pockets of Bcl-xL. We demonstrate that McMD-based dynamic docking is a powerful tool that can be effectively used to study binding mechanisms involving a cryptic site, where ligand binding requires a large conformational change in the protein to occur.

2020 ◽  
F. Javier Aguado ◽  
Raquel Carreira ◽  
Vanesa Hurtado-Nieves ◽  
Miguel G. Blanco

ABSTRACTYen1 and GEN1 are members of the Rad2/XPG family of nucleases that were identified as the first canonical nuclear Holliday junction (HJ) resolvases in budding yeast and humans due to their ability to introduce two symmetric, coordinated incisions on opposite strands of the HJ, yielding nicked DNA products that could be readily ligated. While GEN1 has been extensively characterized in vitro, much less is known about the biochemistry of Yen1. Here, we have performed the first in-depth characterization of purified Yen1. We confirmed that Yen1 resembles GEN1 in many aspects, including range of substrates targeted, position of most incisions they produce or monomeric state in solution. However, we have also observed unexpected alternative processing of substrates, such as nicked HJs and a different conformational preference on intact HJs. Moreover, we demonstrate that Yen1 is endowed with additional nuclease activities, like a nick-specific 5’-3’ exonuclease or HJ arm-chopping that could apparently blur its classification as a canonical HJ resolvase. Despite this, we show that Yen1 fulfills the requirements of a canonical HJ resolvase and hypothesize that its wider array of nuclease activities might contribute to its function in the removal of persistent recombination or replication intermediates.

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