| Full text | |
| Author(s): |
Lima, Angelica Nakagawa
[1, 2]
;
de Oliveira, Ronaldo Junio
[2]
;
Kimus Braz, Antonio Sergio
[1]
;
de Souza Costa, Mauricio Garcia
[3]
;
Perahia, David
[4]
;
Barbour Scott, Luis Paulo
[1]
Total Authors: 6
|
| Affiliation: | [1] Univ Fed ABC, Lab Biol Computac & Bioinformat, Santo Andre, SP - Brazil
[2] Univ Fed Triangulo Mineiro, Inst Ciencias Exatas Nat & Educ, Dept Fis, Lab Biofis Teor, Uberaba, MG - Brazil
[3] Fundacao Oswaldo Cruz, Rio De Janeiro, RJ - Brazil
[4] Ecole Normale Super Paris Saclay, Lab Biol & Pharmacol Appl, Cachan - France
Total Affiliations: 4
|
| Document type: | Journal article |
| Source: | EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS; v. 47, n. 5, p. 583-590, JUL 2018. |
| Web of Science Citations: | 1 |
| Abstract | |
There are two different prion conformations: (1) the cellular natural (PrPC) and (2) the scrapie (PrPSc), an infectious form that tends to aggregate under specific conditions. PrPC and PrPSc are widely different regarding secondary and tertiary structures. PrPSc contains more and longer beta-strands compared to PrPC. The lack of solved PrPSc structures precludes a proper understanding of the mechanisms related to the transition between cellular and scrapie forms, as well as the aggregation process. In order to investigate the conformational transition between PrPC and PrPSc, we applied MDeNM (molecular dynamics with excited normal modes), an enhanced sampling simulation technique that has been recently developed to probe large structural changes. These simulations yielded new structural rearrangements of the cellular prion that would have been difficult to obtain with standard MD simulations. We observed an increase in beta-sheet formation under low pH (4) and upon oligomerization, whose relevance was discussed on the basis of the energy landscape theory for protein folding. The characterization of intermediate structures corresponding to transition states allowed us to propose a conversion model from the cellular to the scrapie prion, which possibly ignites the fibril formation. This model can assist the design of new drugs to prevent neurological disorders related to the prion aggregation mechanism. (AU) | |
| FAPESP's process: | 11/17658-3 - Computational studies on protein folding and applications in the study of enzymes involved in bioethanol production |
| Grantee: | Vitor Barbanti Pereira Leite |
| Support Opportunities: | Regular Research Grants |