Structure-based exploration of an allosteric binding pocket in the NTS1 receptor using bitopic NT(8-13) derivatives and molecular dynamics simulations

2019 ◽  
Vol 25 (7) ◽  
Author(s):  
Ralf Christian Kling ◽  
Carolin Burchardt ◽  
Jürgen Einsiedel ◽  
Harald Hübner ◽  
Peter Gmeiner
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Pocket ◽  
Dynamics Simulations ◽  
Allosteric Binding Pocket

scholarly journals Exchange of water for sterol underlies sterol egress from a StARkin domain

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
George Khelashvili ◽  
Neha Chauhan ◽  
Kalpana Pandey ◽  
David Eliezer ◽  
Anant K Menon
Keyword(s):  
Molecular Dynamics ◽  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Molecular Dynamics Simulations ◽  
Large Scale ◽  
Binding Pocket ◽  
Yeast Cells ◽  
Endoplasmic Reticulum Membrane ◽  
Polar Residues ◽  
Dynamics Simulations

Previously we identified Lam/GramD1 proteins, a family of endoplasmic reticulum membrane proteins with sterol-binding StARkin domains that are implicated in intracellular sterol homeostasis. Here, we show how these proteins exchange sterol molecules with membranes. An aperture at one end of the StARkin domain enables sterol to enter/exit the binding pocket. Strikingly, the wall of the pocket is longitudinally fractured, exposing bound sterol to solvent. Large-scale atomistic molecular dynamics simulations reveal that sterol egress involves widening of the fracture, penetration of water into the cavity, and consequent destabilization of the bound sterol. The simulations identify polar residues along the fracture that are important for sterol release. Their replacement with alanine affects the ability of the StARkin domain to bind sterol, catalyze inter-vesicular sterol exchange and alleviate the nystatin-sensitivity of lam2Δ yeast cells. These data suggest an unprecedented, water-controlled mechanism of sterol discharge from a StARkin domain.

STUDY ON THE INTERACTIONS OF Smac MIMETICS WITH XIAP-BIR3 DOMAIN BY DOCKING AND MOLECULAR DYNAMICS SIMULATIONS

2010 ◽  
Vol 09 (04) ◽  
pp. 797-812 ◽  
Author(s):  
BAOPING LING ◽  
RUI ZHANG ◽  
ZHIGUO WANG ◽  
YONGJUN LIU ◽  
CHENGBU LIU
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Mitochondrial Protein ◽  
Binding Pocket ◽  
Inhibitory Effect ◽  
Inhibitor Of Apoptosis ◽  
Caspase 9 ◽  
Apoptosis Protein ◽  
Smac Mimetics ◽  
Dynamics Simulations

Upon receiving an apoptotic stimulus, the mature mitochondrial protein second mitochondria-derived activator of caspases (Smac)/direct IAP-binding protein with low PI (DIABLO), which could be released from mitochondria into the cytosol together with cytochrome C , specifically binds to inhibitor of apoptosis proteins (IAPs) and relieves the inhibitory effect of caspase, thus promotes cell death. Some artificial small molecules (called Smac mimetics) can mimic the N-terminal four residues Ala1-Val2-Pro3-Ile4 (AVPI) sequence of mitochondrial protein Smac, and competitively bind to X-linked inhibitor of apoptosis protein baculoviral IAP repeats (XIAP-BIR3) domain with caspase-9, which leads to the removal of the inhibition of caspase-9 by XIAP and induce apoptosis. To gain an insight into the nature of XIAP-BIR3 domain recognizing Smac mimetics, we used docking and molecular dynamics simulations methods to study four representative Smac mimetics. The docking results show that the orientations of these backbones of ligands are identical with that of AVPI in the binding pocket. Each ligand corresponds to two competitive conformations, which are called extended and bended conformations. The results of molecular dynamics simulations show that the extended conformation is more stable, and the calculations of energy decomposition reveal that the residue Thr308 makes the strongest interaction with XIAP-BIR3. In addition, Asp309, Glu314, and Trp323 are indispensable for XIAP-BIR3 recognizing and binding Smac mimetics.

scholarly journals Structure-Based Design and Molecular Dynamics Simulations of Pentapeptide AEYTR as a Potential Acetylcholinesterase Inhibitor

2020 ◽  
Vol 20 (4) ◽  
pp. 953
Author(s):  
Vivitri Dewi Prasasty ◽  
Enade Perdana Istyastono
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Acetylcholinesterase Inhibitor ◽  
Acetylcholinesterase Inhibitors ◽  
Binding Pocket ◽  
Screening Protocol ◽  
Acetylcholinesterase Enzyme ◽  
Dynamics Simulations ◽  
Potential Inhibitors ◽  
Free Energy Of Binding

Structure-based virtual screening protocol to identify potent acetylcholinesterase inhibitors was retrospectively validated. The protocol could be employed to examine the potential of designed compounds as novel acetylcholinesterase inhibitors. In a research project designing short peptides as acetylcholinesterase inhibitors, peptide AEYTR emerged as one of the potential inhibitors. This article presents the design of AEYTR assisted by the validated protocol and guided by literature reviews followed by molecular dynamics studies to examine the interactions of the pentapeptide in the binding pocket of the acetylcholinesterase enzyme. The molecular dynamics simulations were performed using YASARA Structure in Google Cloud Platform. The peptide AEYTR was identified in silico as a potent acetylcholinesterase inhibitor with the average free energy of binding (DG) of -19.138 kcal/mol.

scholarly journals Exploring the conformational space of a receptor for drug design: an ERα case study

2020 ◽  
Author(s):  
Melanie Schneider ◽  
Jean-Luc Pons ◽  
Gilles Labesse
Keyword(s):  
Molecular Dynamics ◽  
Drug Design ◽  
Molecular Dynamics Simulations ◽  
Crystal Structures ◽  
Estrogen Receptor Alpha ◽  
Binding Pocket ◽  
Conformational Space ◽  
Toxicity Tests ◽  
Static Structure ◽  
Dynamics Simulations

ABSTRACTMotivationProtein flexibility is challenging for both experimentalists and modellers, especially in the field of drug design. Estrogen Receptor alpha (ERα) is an extensively studied Nuclear Receptor (NR) and a well-known therapeutic target with an important role in development and physiology. It is also a frequent off-target in standard toxicity tests for endocrine disruption. Here, we aim to evaluate the degree to which the conformational space and macromolecular flexibility of this well-characterized drug target can be described. Our approach exploits hundreds of crystallographic structures by means of molecular dynamics simulations and of virtual screening.ResultsThe analysis of hundreds of crystal structures confirms the presence of two main conformational states, known as ‘agonist’ and ‘antagonist’, that mainly differ by the orientation of the C-terminal helix H12 which serves to close the binding pocket. ERα also shows some loop flexibility, as well as variable side-chain orientations in its active site. We scrutinized the extent to which standard molecular dynamics simulations or crystallographic refinement as ensemble recapitulate most of the variability features seen by the array of available crystal structure. In parallel, we investigated on the kind and extent of flexibility that is required to achieve convincing docking for all high-affinity ERα ligands present in BindingDB. Using either only one conformation with a few side-chains set flexible, or static structure ensembles in parallel during docking led to good quality and similar pose predictions. These results suggest that the several hundreds of crystal structures already known can properly describe the whole conformational universe of ERα’s ligand binding domain. This opens the road for better drug design and affinity [email protected]

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