ORCID Profile
0000-0003-3956-3284
Current Organisation
CSIRO Black Mountain Laboratories
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Publisher: Elsevier BV
Date: 12-2021
Publisher: Rockefeller University Press
Date: 21-07-2022
Abstract: Piezo2 is a mechanosensitive ion channel that plays critical roles in sensing touch and pain, proprioception, and regulation of heart rate. Global knockout of Piezo2 leads to perinatal lethality in mice, and Piezo2 gain-of-function mutations are associated with distal arthrogryposis, a disease characterized by congenital joint contractures. Emerging evidence suggests that Piezo channels (Piezo1 and Piezo2) can be regulated by their local membrane environment and particularly by cholesterol and phosphoinositides. To characterize the local Piezo2 lipid environment and investigate key lipid–protein interactions, we carried out coarse-grained molecular dynamics simulations of Piezo2 embedded in a complex mammalian membrane containing & distinct lipid species. We show that Piezo2 alters its local membrane composition such that it becomes enriched with specific lipids, such as phosphoinositides, and forms specific, long-term interactions with a variety of lipids at functionally relevant sites.
Publisher: Proceedings of the National Academy of Sciences
Date: 21-02-2018
Abstract: Voltage-gated sodium channels are integral in electrical signaling within the human body and are key targets for anesthetics and antiepileptic compounds used in surgeries and the treatment of neurological disorders. We have used molecular simulations to determine where a number of these compounds bind inside the pore of a voltage-gated sodium channel to aid the design of new compounds for treating chronic pain, heart conditions, and epilepsy. We uncover two distinct binding sites inside the pore harnessed by neutral and charged drugs, respectively. This explains why so many anesthetic compounds have both neutral and charged forms: The neutral form more easily enters the pore, but the charged form binds more tightly to effectively block the pore and prevent electrical signaling.
Publisher: American Chemical Society (ACS)
Date: 08-01-2014
DOI: 10.1021/BI401576K
Publisher: American Chemical Society (ACS)
Date: 22-04-2014
DOI: 10.1021/CT500003G
Publisher: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 10-2020
Publisher: Elsevier
Date: 2017
DOI: 10.1016/BS.APHA.2017.02.002
Abstract: Voltage-gated ion channels are the target of a range of naturally occurring toxins and therapeutic drugs. There is a great interest in better understanding how these erse compounds alter channel function in order to design the next generation of therapeutics that can selectively target one of the channel subtypes found in the body. Since the publication of a number of bacterial sodium channel structures, molecular dynamics simulations have been invaluable in gaining a high resolution understanding where many of these small molecules and toxins bind to the channels, how they find their binding site, and how they can selectively bind to one channel subtype over another. This chapter summarizes these recent studies to highlight what has been learnt about channel pharmacology using computer simulations and to draw out shared conclusions, focusing separately on toxin-channel interactions and small molecule-channel interactions.
Publisher: Public Library of Science (PLoS)
Date: 26-07-2016
Publisher: Springer Science and Business Media LLC
Date: 13-10-2022
Publisher: Wiley
Date: 16-08-2010
DOI: 10.1002/PROT.22811
Abstract: We present a computationally efficient method for flexible refinement of docking predictions that reflects observed motions within a protein's structural class. Using structural homologs, we derive deformation models that capture likely motions. The models or "replicates" typically align along a rigid core, with a handful of flexible loops, linkers and tails. A few replicates can generate a much larger number of conformers, by exchanging each flexible region independently of the others. In this way, 10 replicates of a protein having 6 flexible regions can be used to generate a million conformations of a molecule. While this has obvious advantages in terms of s ling, the cost of assessing energies at every conformer is prohibitive, particularly when both molecules are flexible. Our approach addresses this combinatorial explosion, using key assumptions to compress the s ling by many orders of magnitude. ReplicOpter can perform hierarchical clustering from a list of rigid docking predictions and find nearby structures to any promising cluster representatives. These predicted complexes can then be refined and rescored. ReplicOpter's scoring function includes a Lennard-Jones potential softened using the Anderson-Chandler-Weeks decomposition, a desolvation term derived from the Atomic Contact Energy function, Coulombic electrostatics, hydrogen bonding, and terms to model pi-pi and pi-cation interactions. ReplicOpter has performed well on several recent CAPRI systems. We are presently benchmarking ReplicOpter on the complete docking benchmark set to fully establish its utility in refining rigid docking predictions and identifying near-native solutions.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Amanda Buyan.