000109078 001__ 109078 000109078 005__ 20230519145448.0 000109078 0247_ $$2doi$$a10.1016/j.bpc.2020.106520 000109078 0248_ $$2sideral$$a122587 000109078 037__ $$aART-2021-122587 000109078 041__ $$aeng 000109078 100__ $$0(orcid)0000-0002-7848-5373$$aCamino, J.D.$$uUniversidad de Zaragoza 000109078 245__ $$aThe role of water in the primary nucleation of protein amyloid aggregation 000109078 260__ $$c2021 000109078 5060_ $$aAccess copy available to the general public$$fUnrestricted 000109078 5203_ $$aThe understanding of the complex conformational landscape of amyloid aggregation and its modulation by relevant physicochemical and cellular factors is a prerequisite for elucidating some of the molecular basis of pathology in amyloid related diseases, and for developing and evaluating effective disease-specific therapeutics to reduce or eliminate the underlying sources of toxicity in these diseases. Interactions of proteins with solvating water have been long considered to be fundamental in mediating their function and folding; however, the relevance of water in the process of protein amyloid aggregation has been largely overlooked. Here, we provide a perspective on the role water plays in triggering primary amyloid nucleation of intrinsically disordered proteins (IDPs) based on recent experimental evidences. The initiation of amyloid aggregation likely results from the synergistic effect between both protein intermolecular interactions and the properties of the water hydration layer of the protein surface. While the self-assembly of both hydrophobic and hydrophilic IDPs would be thermodynamically favoured due to large water entropy contributions, large desolvation energy barriers are expected, particularly for the nucleation of hydrophilic IDPs. Under highly hydrating conditions, primary nucleation is slow, being facilitated by the presence of nucleation-active surfaces (heterogeneous nucleation). Under conditions of poor water activity, such as those found in the interior of protein droplets generated by liquid-liquid phase separation, however, the desolvation energy barrier is significantly reduced, and nucleation can occur very rapidly in the bulk of the solution (homogeneous nucleation), giving rise to structurally distinct amyloid polymorphs. Water, therefore, plays a key role in modulating the transition free energy of amyloid nucleation, thus governing the initiation of the process, and dictating the type of preferred primary nucleation and the type of amyloid polymorph generated, which could vary depending on the particular microenvironment that the protein molecules encounter in the cell. 000109078 536__ $$9info:eu-repo/grantAgreement/ES/MCIU-MINECO-FEDER/BFU2015-64119-P$$9info:eu-repo/grantAgreement/ES/MCIU-MINECO-FEDER/PGC2018-096335-B-100$$9info:eu-repo/grantAgreement/ES/MCIU-MINECO-FEDER/RYC-2012-12068 000109078 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/ 000109078 590__ $$a3.628$$b2021 000109078 592__ $$a0.606$$b2021 000109078 594__ $$a4.5$$b2021 000109078 591__ $$aBIOPHYSICS$$b31 / 72 = 0.431$$c2021$$dQ2$$eT2 000109078 593__ $$aOrganic Chemistry$$c2021$$dQ2 000109078 591__ $$aCHEMISTRY, PHYSICAL$$b91 / 165 = 0.552$$c2021$$dQ3$$eT2 000109078 593__ $$aBiophysics$$c2021$$dQ2 000109078 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b180 / 297 = 0.606$$c2021$$dQ3$$eT2 000109078 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion 000109078 700__ $$aGracia, P.$$uUniversidad de Zaragoza 000109078 700__ $$0(orcid)0000-0002-9138-6687$$aCremades, N.$$uUniversidad de Zaragoza 000109078 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000109078 773__ $$g269 (2021), 106520 [10 pp]$$pBiophys. chemist.$$tBiophysical Chemistry$$x0301-4622 000109078 8564_ $$s811948$$uhttps://zaguan.unizar.es/record/109078/files/texto_completo.pdf$$yPostprint 000109078 8564_ $$s1015960$$uhttps://zaguan.unizar.es/record/109078/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint 000109078 909CO $$ooai:zaguan.unizar.es:109078$$particulos$$pdriver 000109078 951__ $$a2023-05-18-14:40:59 000109078 980__ $$aARTICLE