Amyloid cross-seeding between Ab and hIAPP in relation to the pathogenesis of Alzheimer and type 2 diabetes

Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.

Development of a radical polymerization algorithm for molecular dynamics simulations of antifreezing hydrogels with double-network structures

The development and understanding of antifreezing hydrogels are crucial both in principle and practice for the design and delivery of new materials.The current antifreezing mechanisms in hydrogels are almost exclusively derived from their incorporation of antifreezing additives,rather than from the inherent properties of the polymers themselves.Moreover,developing a computational model for the independent yet interconnected double-network(DN)structures in hydrogels has proven to be an exceptionally difficult task.Here,we develop a multiscale simulation platform,integrating‘random walk reactive polymerization’(RWRP)with molecular dynamics(MD)simulations,to computationally construct a physically-chemically linked PVA/PHEAA DN hydrogels from monomers that mimic a radical polymerization and to investigate water structures,dynamics,and interactions confined in PVA/PHEAA hydrogels with various water contents and temperatures,aiming to uncover antifreezing mechanism at atomic levels.Collective simulation results indicate that the antifreezing property of PVA/PHEAA hydrogels arises from a combination of intrinsic,strong water-binding networks and crosslinkers and tightly crosslinked and interpenetrating double-network structures,both of which enhance polymer-water interactions for competitively inhibiting ice nucleation and growth.These computational findings provide atomic-level insights into the interplay between polymers and water molecules in hydrogels,which may determine their resistance to freezing.

Activation mechanisms of clinically distinct B-Raf V600Eand V600K mutants

Dear Editor,B-Raf,the main effector of Ras in the mitogen-activated protein kinase(MAPK)pathway,is among the most highly mutated kinases in human cancer[1].About 40%-60%of melanoma patients harbor B-Raf mutations,of which∼90%involve V600E and V600K.B-RafV600E is more frequent(60%-80%)than B-RafV600K(10%-30%).Substitution of a Val codon by Glu requires a single nucleotide change,whereas Val to Lys requires two[2].This is in line with melanoma patients harboring the V600K mutation,who usually suffer from higher sun exposure that may induce increased DNA damage[3].Since both mutations occur at the same position of the kinase domain and are mutated to charged residues,it was believed that the B-Raf V600E and V600K mutantswould share a similar behavior,and in clinical trials,patients with V600E and V600K mutations have been recruited into the same cohort.

A multiscale polymerization framework towards network structure and fracture of double-network hydrogels

Double-network(DN)hydrogels,consisting of two contrasting and interpenetrating polymer networks,are considered as perhaps the toughest soft-wet materials.Current knowledge of DN gels from synthesis methods to toughening mechanisms almost exclusively comes from chemically-linked DN hydrogels by experiments.Molecular modeling and simulations of inhomogeneous DN structure in hydrogels have proved to be extremely challenging.Herein,we developed a new multiscale simulation platform to computationally investigate the early fracture of physically-chemically linked agar/polyacrylamide(agar/PAM)DN hydrogels at a long timescale.A“random walk reactive polymerization”(RWRP)was developed to mimic a radical polymerization process,which enables to construct a physically-chemically linked agar/PAM DN hydrogel from monomers,while conventional and steered MD simulations were conducted to examine the structural-dependent energy dissipation and fracture behaviors at the relax and deformation states.Collective simulation results revealed that energy dissipation of agar/PAM hydrogels was attributed to a combination of the pulling out of agar chains from the DNs,the disruption of massive hydrogen bonds between and within DN structures,and the strong association of water molecules with both networks,thus explaining a different mechanical enhancement of agar/PAM hydrogels.This computational work provided atomic details of network structure,dynamics,solvation,and interactions of a hybrid DN hydrogel,and a different structural-dependent energy dissipation mode and fracture behavior of a hybrid DN hydrogel,which help to design tough hydrogels with new network structures and efficient energy dissipation modes.Additionally,the RWRP algorithm can be generally applied to construct the radical polymerization-produced hydrogels,elastomers,and polymers.