Biology subjects

Genjo, T.

Publications and source records attributed to Genjo, T..

3 recordsLinked to original sources

bioRxiv2018

Self-assembly of polymer-encased lipid nanodiscs and membrane protein reconstitution

The absence of detergent and curvature makes nanodiscs to be excellent membrane mimetics. The lack of structural and mechanistic model of polymer-encapsulated lipid-nanodiscs limits their use to study the structure, dynamics and function of membrane proteins. In this study, we parametrized and optimized the coarse-graining (CG) bead-mapping for two differently charged and functionalized copolymers, namely styrene-maleic acid (SMAEA) and polymethacrylate (PMAQA), for the Martini force-field framework and showed nanodisc formation (< 8 nm diameter) on a time scale of tens of microseconds using molecular dynamics (MD) simulation. Structural models of ~ 2.0 or 4.8 kDa PMAQA and ~2.2 kDa SMAEA polymer based lipid-nanodiscs highlights the importance of polymer chemical structure, size and polymer:lipid molar ratio in the optimization of nanodisc structure. The ideal spatial arrangement of polymers in nanodisc, nanodisc size and thermal stability obtained from our MD simulation correlates well with the experimental observations. The polymer-nanodisc were tested for the reconstitution of single-pass or multi-pass transmembrane proteins. We expect this study to be useful in the development of novel polymer based lipid-nanodiscs and for the structural studies of membrane proteins. TOC GRAPHICS O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/476556v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@ae71c6org.highwire.dtl.DTLVardef@af961borg.highwire.dtl.DTLVardef@1a7e6c3org.highwire.dtl.DTLVardef@1f4a9a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2018

Alzheimer’s Amyloid-Beta Intermediates Generated by Polymer-Nanodiscs

Polymethacrylate-copolymer (PMA) encased lipid-nanodiscs (~10 nm) and macro-nanodiscs (>15 nm) are used to study A{beta}1-40 aggregation. We demonstrate that PMA-nanodiscs form a ternary association with A{beta} and regulate its aggregation kinetics by trapping intermediates. Results demonstrating reduced neurotoxicity of nanodisc-bound A{beta} oligomers are also reported.

biophysics↗

bioRxiv2018

Cationic polymethacrylate-copolymer acts as an agonist for beta-amyloid and antagonist for amylin fibrillation

In human, amyloid-beta (A{beta}) and islet amyloid polypeptide (hIAPP) aggregations are linked to Alzheimers disease and Type-2 Diabetes, respectively. There is significant interest in better understanding the aggregation process by using chemical tools. Here, we show the ability of a cationic polymethacrylate-copolymer (PMAQA) to quickly induce {beta}-hairpin structure and promote fibrillation in A{beta}40, and to constrain the conformational plasticity of hIAPP for several days and inhibit its aggregation at sub-micromolar concentrations. NMR experiments and atomistic molecular dynamics simulations reveal that PMAQA electrostatically interacts with A{beta}40s Glu22 and Asp23 followed by {beta}-sheet induction while it binds strongly to the closest proximity of amyloid core domain (NFGAIL) of hIAPP and restrain its structural rearrangement. This study provides a valuable approach to develop polymer-based anti-amyloid inhibitors that may diminish the population of intermediates of A{beta}40 or hIAPP.

biophysics↗