Molecular dynamics simulations of the calmodulin-induced α-helix in the SK2 calcium-gated potassium ion channel

The family of small-conductance Ca2+-activated potassium ion channels (SK channels) is composed of four members (SK1, SK2, SK3, and SK4) involved in neuron-firing regulation. The gating of these channels depends on the intracellular Ca2+ concentration, and their sensitivity to this ion is provided by calmodulin (CaM). This protein binds to a specific region in SK channels known as the calmodulin-binding domain (CaMBD), an event which is essential for their gating. While CaMBDs are typically disordered in the absence of CaM, the SK2 channel subtype displays a small prefolded α-helical region in its CaMBD even if CaM is not present. This small helix is known to turn into a full α-helix upon CaM binding, although the molecular-level details for this conversion are not fully understood yet. In this work, we offer new insights on this physiologically relevant process by means of enhanced sampling, atomistic Hamiltonian replica exchange molecular dynamics simulations, providing a more detailed understanding of CaM binding to this target. Our results show that CaM is necessary for inducing a full α-helix along the SK2 CaMBD through hydrophobic interactions with V426 and L427. However, it is also necessary that W431 does not compete for these interactions; the role of the small prefolded α-helix in the SK2 CaMBD would be to stabilize W431 so that this is the case. In conclusion, our findings provide further insight into a key interaction between CaM and SK channels that is important for channel sensitivity to Ca2+.The authors thank Donostia International Physics Center (DIPC) for providing access to its computational resources. We acknowledge financial support from the Department of Education, Universities, and Research of the Basque Government and the University of the Basque Country (IT1165-19, KK-2020/00110, and IT1707-22), from the Spanish Ministry of Science and Innovation (projects PID2021-128286NB-100, PID2019-105488GB-I00, TED2021-132074B-C32, and RTI2018-097839-B-100) and from FEDER funds

Magnons and magnetic fluctuations in atomically thin MnBi2Te4

MnBi2Te4, referred to as MBT, is a van der Waals material combining topological electron bands with magnetic order. Here, Lujan et al study collective spin excitations in MBT, and show that magnetic fluctuations increase as samples reduce in thickness, implying less robust magnetic order. Electron band topology is combined with intrinsic magnetic orders in MnBi2Te4, leading to novel quantum phases. Here we investigate collective spin excitations (i.e. magnons) and spin fluctuations in atomically thin MnBi2Te4 flakes using Raman spectroscopy. In a two-septuple layer with non-trivial topology, magnon characteristics evolve as an external magnetic field tunes the ground state through three ordered phases: antiferromagnet, canted antiferromagnet, and ferromagnet. The Raman selection rules are determined by both the crystal symmetry and magnetic order while the magnon energy is determined by different interaction terms. Using non-interacting spin-wave theory, we extract the spin-wave gap at zero magnetic field, an anisotropy energy, and interlayer exchange in bilayers. We also find magnetic fluctuations increase with reduced thickness, which may contribute to a less robust magnetic order in single layers.We thank Chao Lei, B. Wieder, A. Ernst, and M. G. Vergniory for helpful discussions. This research was primarily supported by the National Science Foundation through the Center for Dynamics and Control of Materials: an NSF MRSEC under Cooperative Agreement No. DMR-1720595, which also supported the facility used in sample preparation. Additional support from NSF DMR-1949701 and DMR-2114825 is gratefully acknowledged by G.A.F. This work was performed in part at the Aspen Center for Physics, which is supported by the National Science Foundation grant PHY-1607611. A.L. acknowledges support from the funding grant: PID2019-105488GB-I00. Z.Y. and R.H. acknowledge support by the NSF CAREER Grant No. DMR-1760668 and NSF Grant No. DMR-2104036. X.L. gratefully acknowledges the Welch Foundation grant F-1662 for support in sample preparation. Work at ORNL was supported by the U.S. Department of Energy, Office of Science, Basic Energy Sciences, Materials Sciences and Engineering Division. M. R-V. was supported by LANL LDRD Program and by the U.S. Department of Energy, Office of Science, Basic Energy Sciences, Materials Sciences and Engineering Division, Condensed Matter Theory Program. L.-J.C. and S.-F.L. were primarily funded by the Ministry of Science and Technology 105-2112-M-001-031-MY3 in Taiwan, and the collaboration with UT-Austin is facilitated by the Air Force Office of Scientific Research under award number FA2386-21-1-4067. Partial funding for L.-J.C. while visiting UT-Austin was provided by a Portugal-UT collaboration grant

An Epilepsy-Causing Mutation Leads to Co-Translational Misfolding of the Kv7.2 Channel

BACKGROUND: The amino acid sequence of proteins generally carries all the necessary information for acquisition of native conformations, but the vectorial nature of translation can additionally determine the folding outcome. Such consideration is particularly relevant in human diseases associated to inherited mutations leading to structural instability, aggregation, and degradation. Mutations in the KCNQ2 gene associated with human epilepsy have been suggested to cause misfolding of the encoded Kv7.2 channel. Although the effect on folding of mutations in some domains has been studied, little is known of the way pathogenic variants located in the calcium responsive domain (CRD) affect folding. Here, we explore how a Kv7.2 mutation (W344R) located in helix A of the CRD and associated with hereditary epilepsy interferes with channel function. RESULTS: We report that the epilepsy W344R mutation within the IQ motif of CRD decreases channel function, but contrary to other mutations at this site, it does not impair the interaction with Calmodulin (CaM) in vitro, as monitored by multiple in vitro binding assays. We find negligible impact of the mutation on the structure of the complex by molecular dynamic computations. In silico studies revealed two orientations of the side chain, which are differentially populated by WT and W344R variants. Binding to CaM is impaired when the mutated protein is produced in cellulo but not in vitro, suggesting that this mutation impedes proper folding during translation within the cell by forcing the nascent chain to follow a folding route that leads to a non-native configuration, and thereby generating non-functional ion channels that fail to traffic to proper neuronal compartments. CONCLUSIONS: Our data suggest that the key pathogenic mechanism of Kv7.2 W344R mutation involves the failure to adopt a configuration that can be recognized by CaM in vivo but not in vitroThe Government of the Autonomous Community of the Basque Country (IT1165-19 and KK-2020/00110) and the Spanish Ministry of Science and Innovation (RTI2018-097839-B-100 to A.V. and FIS2016-76617-P to A.B.) and FEDER funds and the US National Institute of Neurological Disorders (NINDS) and Stroke Research Project Grant (R01NS083402 to H.J.C.) provided financial support for this work. E.N. and A.M-M. are supported by predoctoral contracts from the Basque Government administered by University of the Basque Country. C.M. was supported by the Basque Government through a Basque Excellence Research Centre (BERC) grant administered by Fundación Biofisika Bizkaia (FBB). J.U. was partially supported by BERC funds. O.R.B. was supported by the Basque Government through a BERC grant administered by Donostia International Physics Center. J.Z. and H.J.C. was supported by the NINDS Research Project Grant #R01NS083402 (PI: H.J.C.)

Magnetic order and magnetic anisotropy in two-dimensional ilmenenes

Iron ilmenene is a new two-dimensional material that has recently been exfoliated from the naturally occurring iron titanate found in ilmenite ore, a material that is abundant on the earth's surface. In this work, we theoretically investigate the structural, electronic and magnetic properties of 2D transition- metal-based ilmenene-like titanates. The study of magnetic order reveals that these ilmenenes usually present intrinsic antiferromagnetic coupling between the 3d magnetic metals decorating both sides of the Ti–O layer. Furthermore, the ilmenenes based on late 3d brass metals, such as CuTiO3 and ZnTiO3, become ferromagnetic and spin compensated, respectively. Our calculations which include spin–orbit coupling reveal that the magnetic ilmenenes have large magnetocrystalline anisotropy energies when the 3d shell departs from being either filled or half-filled, with their spin orientation being out-of-plane for elements below half-filling of 3d states and in-plane above. These interesting magnetic properties of ilmenenes make them useful for future spintronic applications because they could be synthesized as already realized in the iron case.This work has been supported by the Spanish Ministry of Science and Innovation through grants PID2019-105488GB-I00, TED2021-132074B-C32 and PCI2019-103657. We acknowledge nancial support by the European Commission from the MIRACLE (ID 964450), NaturSea-PV (ID 101084348), and NRG- STORAGE project (GA 870114). The Basque Government sup- ported this work through Project No. IT-1569-22. M. A. was supported by the Spanish Ministry of Science and Innovation through the FPI PhD Fellowship BES-2017-079677. R. H. A.-T. acknowledges the postdoctoral contract from the Donostia International Physics Center