Spectacular induced-fit process for guest binding by a calix[6]arene Zn(ii) funnel complex

2008 ◽  
Vol 6 (21) ◽  
pp. 3930 ◽  
Author(s):  
David Coquière ◽  
Jérôme Marrot ◽  
Olivia Reinaud
Keyword(s):  
Induced Fit ◽  
Guest Binding

SAMPL7 TrimerTrip Host-Guest Binding Poses and Binding Affinities from Spherical-Coordinates-Biased Simulations

2020 ◽  
Author(s):  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Computational Modelling ◽  
Free Energy Calculations ◽  
Energy Estimates ◽  
Binding Affinities ◽  
Spherical Coordinates ◽  
Collective Variables ◽  
Guest Binding ◽  
Starting Point ◽  
Sampl Challenge

Host-guest binding remains a major challenge in modern computational modelling. The newest 7<sup>th</sup> statistical assessment of the modeling of proteins and ligands (SAMPL) challenge contains a new series of host-guest systems. The TrimerTrip host binds to 16 structurally diverse guests. Previously, we have successfully employed the spherical coordinates as the collective variables coupled with the enhanced sampling technique metadynamics to enhance the sampling of the binding/unbinding event, search for possible binding poses and predict the binding affinities in all three host-guest binding cases of the 6<sup>th</sup> SAMPL challenge. In this work, we employed the same protocol to investigate the TrimerTrip host in the SAMPL7 challenge. As no binding pose is provided by the SAMPL7 host, our simulations initiate from randomly selected configurations and are proceeded long enough to obtain converged free energy estimates and search for possible binding poses. The predicted binding affinities are in good agreement with the experimental reference, and the obtained binding poses serve as a nice starting point for end-point or alchemical free energy calculations.

Association/dissociation Mechanisms of Intrinsically Disordered Region of Protein Beyond Conformational Selection and Induced Fit

2019 ◽  
Author(s):  
Duy Phuoc Tran ◽  
Akio Kitao
Keyword(s):  
Free Energy ◽  
Transcriptional Activation ◽  
Binding Free Energy ◽  
Energy Structure ◽  
Induced Fit ◽  
Hydrogen Bond Formation ◽  
Conformational Selection ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Region ◽  
Dissociation Mechanisms

<p>We investigate association and dissociation mechanisms of a typical intrinsically disordered region (IDR), transcriptional activation subdomain of tumor repressor protein p53 (TAD-p53) with murine double-minute clone 2 protein (MDM2). Using the combination of cycles of association and dissociation parallel cascade molecular dynamics, multiple standard MD, and Markov state model, we are successful in obtaining the lowest free energy structure of MDM2/TAD-p53 complex as the structure very close to that in crystal without prior knowledge. This method also reproduces the experimentally measured standard binding free energy, and association and dissociation rate constants solely with the accumulated MD simulation cost of 11.675 μs, in spite of the fact that actual dissociation occurs in the order of a second. Although there exist a few complex intermediates with similar free energies, TAD-p53 first binds MDM2 as the second lowest free energy intermediate dominantly (> 90% in flux), taking a form similar to one of the intermediate structures in its monomeric state. The mechanism of this step has a feature of conformational selection. In the second step, dehydration of the interface, formation of π-π stackings of the side-chains, and main-chain relaxation/hydrogen bond formation to complete α-helix take place, showing features of induced fit. In addition, dehydration (dewetting) is a key process for the final relaxation around the complex interface. These results demonstrate a more fine-grained view of the IDR association/dissociation beyond classical views of protein conformational change upon binding.</p>

Cambiarenes: Single-Step Synthesis and Anion Binding of a Clip- Shaped Macrocycle with a Redox-Active Core

2019 ◽  
Author(s):  
Riley J. Petersen ◽  
Brett J. Rozeboom ◽  
Shalisa Oburn ◽  
Nolan Blythe ◽  
Tanner Rathje ◽  
...  
Keyword(s):  
Electron Density ◽  
Single Step ◽  
Anion Binding ◽  
Host Molecule ◽  
Selective Binding ◽  
The Core ◽  
Redox Active ◽  
Active Core ◽  
Guest Binding

<div>We report the synthesis of a novel macrocyclic host molecule that forms in a single step from commercially available starting materials. The core of the macrocycle backbone possesses two quinone rings and, thus, is redox-active. Host-guest binding involving the clip-shaped cavity indicates selective binding of pyridine <i>N</i>-oxides based of the electron density of and steric bulk of the anionic oxygen.</div>

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