Journal article
How do salt and lipids affect conformational dynamics of Aβ42 monomers in water?
PHYSICAL CHEMISTRY CHEMICAL PHYSICS, v 25(3), p2566
18 Jan 2023
PMID: 36602150
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
It is well established that amyloid beta-protein (A beta) self-assembly is involved in triggering of Alzheimer's disease. On the other hand, evidence of physiological function of A beta interacting with lipids has only begun to emerge. Details of A beta-lipid interactions, which may underlie physiological and pathological activities of A beta, are not well understood. Here, the effects of salt and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipids on conformational dynamics of A beta 42 monomer in water are examined by all-atom molecular dynamics (MD). We acquired six sets of 250 ns long MD trajectories for each of the three lipid concentrations (0, 27, and 109 mM) in the absence and presence of 150 mM salt. Ten replica trajectories per set are used to enhance sampling of A beta 42 conformational space. We show that salt facilitates long-range tertiary contacts in A beta 42, resulting in more compact A beta 42 conformations. By contrast, addition of lipids results in lipid-concentration dependent A beta 42 unfolding concomitant with enhanced stability of the turn in the A21-A30 region. At the high lipid concentration, salt enables the N-terminal region of A beta 42 to form long-range tertiary contacts and interact with lipids, which results in formation of a parallel beta-strand. A beta 42 forms stable lipid-protein complexes whereby the protein is adhered to the lipid cluster rather than embedded into it. We propose that the inability of A beta 42 monomer to get embedded into the lipid cluster may be important for facilitating repair of leaks in the blood-brain barrier without penetrating and damaging cellular membranes.
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Details
- Title
- How do salt and lipids affect conformational dynamics of Aβ42 monomers in water?
- Publication Details
- PHYSICAL CHEMISTRY CHEMICAL PHYSICS, v 25(3), p2566
- Publisher
- ROYAL SOC CHEMISTRY; CAMBRIDGE
- Grant note
- This work has been supported by the National Science Foundation through the grant numbers MCB-1817650 and OAC-1919691. MD simulations were performed on hardware supported by Drexel's University Research Computing Facility. The authors acknowledge fruitful discussions with Prof. Reinhard Schweitzer-Stenner on the comparison of MD-derived and experimental J-coupling constants.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:000907636400001
- Scopus ID
- 2-s2.0-85146269506
- Other Identifier
- 991021861300904721
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- Web of Science research areas
- Chemistry, Physical
- Physics, Atomic, Molecular & Chemical