Hoạt động
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Seminar
| Seminar Vật lý lý thuyết và Vật lý tính toán:
| | Tên báo cáo | Molecular simulations of intrinsically disordered proteins involved in human diseases
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| Người trình bày | Dr. Tâp Ha-Duong
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| Cơ quan | University of Paris-Sud
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| Ngày | Thứ Tư, 07-12-2016
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| Giờ | 10:00 AM
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| Địa điểm | Phòng 202 (Thư viện), Viện Vật lý, 10 Đào Tấn, Ba Đình, Hà Nội
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| Tóm tắt | Intrinsically disordered proteins (IDP) are polypeptides containing long regions (more than 30 consecutive residues) that lack stable secondary structures. Bioinformatics analyses of several proteomes indicate that more than one third of eukaryotic proteins are intrinsically disordered. Many of them are involved in signalling pathways or regulation processes, and are considered as critical hubs in proteins interaction networks [1]. Overexpressions, mutations or dysfunctions of these proteins are involved in many human diseases, including cancer, diabetes, cardiovascular and neurodegenerative disorders [2]. Thus, a very promising route for the development of new drugs against these diseases is to interfere with the IDP-protein interactions.
IDP can specifically interact with several proteins thanks to their intrinsically disordered region (IDR) which is highly flexible and capable of adopting various conformations to fit their partner binding sites. More specifically, many IDR undergo a disorder-to-order transition upon binding, towards 𝛼-helical or β-strand conformations called Molecular Recognition Features (MoRF) [3]. Depending on their sequence and environment, MoRF either fold during the binding process (coupled folding and binding mechanism), or transiently pre-exist before interacting with their binding site (conformational selection mechanism) [4].
However, IDP and their MoRF are difficult to be structurally characterized using experimental approaches, due to their high flexibility. Very often, the atomic coordinates of IDR are absent from the Protein Data Bank crystallographic structures. The lack of a homogeneous conformation in solution also makes the NMR approaches very demanding. Thus, providing a comprehensive description of IDP conformational ensembles is still a challenging task [5]. In this context, computational tools are complementary approaches that can considerably help to elucidate the structural determinants of IDP and their interactions with other proteins.
This presentation will address the case of one IDP under study in our group, the Aβ peptide involved in the Alzheimer's disease [6]. It will be shown how enhanced molecular dynamics simulations enable to explore the IDP ensemble of conformations and to detect those, rich in secondary structures, that are prone to form protein assemblies. We believe that these theoretical studies can guide the design of new therapeutic molecules targeting and inhibiting IDP.
References
[1] V.N. Uversky, Int. J. Biochem. Cell Biol. 2011, 43, 1090-1103.
[2] V.N. Uversky, BMC Genomics. 2009, 10, S7.
[3] A. Mohan et al., J. Mol. Biol. 2006, 362, 1043-1059.
[4] L.M. Espinoza-Fonseca, Biochem. Biophys. Res. Commun. 2009, 382, 479-482.
[5] T. Mittage and J.D. Forman-Kay, Curr. Opin. Struct. Biol. 2007, 17, 3-14.
[6] C.A. McLean, Ann. Neurol. 1999, 46, 860-866.
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| Người chủ trì | Trịnh Xuân Hoàng
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