Nghiên cứu cấu trúc và động lực học của các oligomer amyloid beta bằng mô phỏng

DẠI HỌC Quốc GIA TP Hồ CHÍ MINH TRƯỜNG ĐẠI HỌC BÁCH KHOA NGUYÊN HOÀNG LINH NGHIÊN CỨU CÂU TRÚC VÀ ĐỘNG Lực HỌC CỦA CÁC OLIGOMER AMYLOID BETA BẰNG MÔ PHỎNG Ngành: VẬT LÝ KỸ THUẬT Mã số ngành: 9520401 Phản biện độc lập: Phản biện độc lập: Phản biện: GS TSKH Lê Văn Hoàng Phản biện: PGS TS Nguyễn Thị Thúy Hằng Phản biện: TS Nguyễn Thụy Việt Phương NGƯỜI HƯỚNG DẪN: GS.TSKH MAI XUÂN LÝ PGS.TS HUỲNH QUANG LINH DẠI HỌC Qưóc GIA TP Hồ CHÍ MINH TRƯỜNG ĐẠI HỌC BÁCH KHOA NGUYỄN HỒNG LINH NGHIÊN CỨU CẤU TRÚC VÀ ĐỘNG Lực HỌC CỦA CÁC OLIGOMER AMYLOID BETA BẰNG MÔ PHỎNG LUẬN ÁN TIẾN Sĩ TP HỔ CHÍ MINH - 2022 LỜI CAM ĐOAN Tác giả xin cam đoan cơng trình nghiên cứu thân tác giả hướng dẫn GS.TSKH Mai Xuân Lý, PGS.TS Huỳnh Quang Linh cộng tác với đồng nhóm nghiên cứu Các kết nghiên cứu kết luận luận án trung thực, không chép từ nguồn dưói hình thức Việc tham khảo nguồn tài liệu thực trích dẫn ghi nguồn tài liệu tham khảo quy định Tác giả luận án Nguyễn Iloàng Linh Nguyễn Hồng Linh i Tóm tắt nội dung Mặc dù trải qua nhiều năm nghiên cứu chuyên sâu, nguyên nhân chế gây Bệnh Alzheimer (AD, Alzheimer's disease) cịn nhiều tranh luận Sự tích tụ q mức peptide Amyloid beta (A/ỉ, Amyloid beta) dạng kết tụ làm tơn hại tế bào thần kinh sở giả thuyêt tâng amyloid (amyloid cascade), đưa để giải thích nguyên nhân gây AD Vì vậy, cấu trúc dạng kết tụ A/3 đóng vai trị tối quan trọng hiểu biết chế AD Ban đầu người ta cho cấu trúc sợi có độc tính thí nghiệm gần cho thấy oligomer có độc tính cao Do đặc tính trật tự peptide A/5 tốc độ kết tụ cao, thời gian sống tương đối ngắn oligomer A/3 cấu trúc chúng gần thu phương pháp thực nghiệm Trong số oligomer bậc thấp A/?, trimer, tetramer, hexamer dodecamer Amyloid beta 42 (A/h-42, Amyloid beta 42) có độc tính thần kinh cao so với dạng kêt tụ khác A/? Phương pháp mô động lực học phân tử thành công việc thu tính chất động học, cấu trúc cho monomer A/3 tương tác dimer Ajổ màng tế bào thần kinh Vì lý này, phương pháp mơ phóng động lực học phân tử sít dụng ( rong luận án để khảo sát tetramer trimer A/3[ 42 hai số dạng oligomer nhỏ mang độc tính với tế bào thần kinh cao A/3 Các cấu trúc thu từ mơ đánh giá tính ổn định so sánh với mơ hình sợi từ thực nghiệm Những kết thu góp phần giải thích oligomer bậc thấp A/3 có cấu trúc phân tử khác biệt với sựi hoàn chinh Một ảnh hưởng đầu độc tế bào thần kinh oligomer A/3 khả làm thung màng tế bào mà điển hình dodecamer A/?1 42 Do đó, ảnh hưởng dodecamer A/3i 42 sợi hoàn chỉnh A/31 42 lên cấu trúc màng tế bào thần kinh ó bệnh nhân Alzheimer nghiên cứu luận án Các kết luận án cho thấy tetramer A/?i-42 hình thành nên nhiều cấu trúc ổn định có tính đa hình, điều giải thích diện nhiều lộ trình kết tụ khác A/3 Các cấu trúc tetramer thu có cấu tạo bao gồm chuỗi vả lõi, tetramer khác biệt đáng kể với cấu trúc sợi hoàn chỉnh Tương tác với nước lý tetramer bó chặt khô không gian bên protein sợi Các tính chất, hố lý mơ hình tất nguyên tứ luận án phù hợp với khám phá thực nghiệm dự đoán lý thuyết có Do đó, luận án cung cấp mơ hình cấu trúc tetramer A/3ỵ 42 cho nghiên cứu thiết kế oligomer bậc cao ii Vói trimer A/?1 42, mơ động lực học phân tử kết hợp phương pháp trao đổi sử dụng mơ hình tất ngun tử với hai cấu hình ban đầu khác tiến hành gồm i) cấu hình tạo mơ docking monomer vào dimer A/?1 42 (mô 1), biểu diễn oligomer tạo cách kết hợp monomer lại với nhau; ii) cấu hình tách từ cấu trúc sợi hồn chỉnh lấy từ thực nghiệm (mơ 2), biểu diễn oligomer xếp cấu trúc trạng thái cân có dạng sợi Kết luận án chứng minh mô trimer A/Ĩ1-42 hình thành cấu trúc dạng thùng fi nhó, cho thấy khả hình thành tự phát vùng cấu trúc có dạng tương tự kênh dẫn ion xuyên màng Các cấu trúc có tính chất khác với kết từ sợi hồn chỉnh (mơ 2), c peptide A/31-42 ổn định, thay đối so với cấu hình ban đầu, điều khơng phát mô cấu trúc dạng thùng Ị3 xuất tự phát kết luận án lần quan sát thấy từ nghiên cứu mơ Ngồi ra, trimer A/h 42 hình thành lổ xuyên cấu trúc đủ lớn để chứa phân tử nước ion Ca2+ Anh hương dodecamer sợi hoàn chỉnh A/Ỉ1 42 lên màng lipid kép nhiều thành phần, tương tự rnơ hình màng tế bào phát bệnh nhân AD mô phương pháp động lực học phân tử Do thời gian mơ phóng ngắn, hình thành lỗ xun màng tế bào khơng dược phát hiện, cung cấp thông tin hữu ích kiện ban đầu trình Nghĩa lả, luận án chứng minh dodecamer làm biến dạng màng lipid kép nhiều sựi, diều cho thấy kênh ion xuyên mảng dễ dàng hình thành có mặt oligomer Dựa kết q này, chúng tơi dự đốn oligomer A/h-42 có độc tính với tế bào thần kinh cao sợi hồn chính, quan sát bơi thực nghiệm Ngồi ra, tương tác A/3 màng tế bào thần kinh phát bị chi phối lực đẩy tĩnh điện A/3 lipid GM1 Modul uốn nén diện tích màng tế bào thần kinh khơng có mặt A/3 phù hợp tốt vói thực nghiêm Dodecamer A/h-42 dự đoán làm tăng modul nén diện tích, có hiệu ứng lên modul uốn Do tương tác yếu với màng tế bào thần kinh, sợi hồn chỉnh A/31 42 làm thay đổi khơng đáng kể tính chất đàn hồi màng tế bào thần kinh Các kết thu cho tetramer, trimer dodecamer A/?1 42 cho thấy phương pháp mô dùng luận án hợp lý việc nghiên cứu cấu trúc tương tác oligomer A/51-42 với màng té bào thần kinh Những oligomer khơng có cấu trúc xác định, phù hựp với kết thực nghiệm Từ phân tích tính chất hố lý cùa tetramer, trimer so sánh với sựi hoàn chỉnh cùa A/J1-42, tác giả đề xuất giả thuyết khác biệt cấu trúc dạng kết tụ oligomer A/3 sợi hoàn chỉnh Tương tác dodecamer, sợi A/?1 -42 màng tế bào thần kinh quan sát kiện ban đầu chế phân tứ tương tác góp phần làm sáng tò khả đầu độc, làm chết tế bào thần kinh dạng kết tụ oligomer Nguyễn Hoàng Linh iii Abstract Despite of many years of intensive research, little is known about cause and mecha­ nism of Alzheimer’s disease (AD) Excess accumulation of amyloid beta (A/?) peptides and their aggregation lead to ruin the neuronal cells being the basis of an amyloid cascade hypothesis, which attempts to explain the causes of AD Therefore, the struc­ ture of A/3 aggregations play crucial role in the knowledge about mechanism of AD It was initially thought that fibrils were toxic, but recent experiments have shown that oligomers arc more toxic Duc to intrinsically disordered character of Afi monomers, the high aggregation rate and transient life time of AjS oligomers, their structures arc vir­ tually impossible to solve using experimental methods The trimer, tetramer, hexamer, and dodecamer of Ajỡi 42 have more neuronal toxicity than other aggregation forms of A/? The molecular dynamics method has succeeded to obtain dynamic and structural properties of monomer A/3 as well as the interaction of dimer A/3 and neuronal mem­ brane For this reason, we used molecular dynamics simulations to extensively search for the conformational space of A/Ĩ1-42 tetramer and trimer Obtained structures were subsequently tested for stability and compared with proposed experimental fibril mod­ els The neuronal membrane pore forming is one of the neuronal toxicities caused by oligomer Afỉ Therefore, the impact of dodecamer A/?i-42 and mature fibril A/?1 421 on the structural stability of neuron membrane from patients of AD is also investigated in this dissertation Our results show that Afli 42 tetramer can form multiple stable structures with poly­ morphism property, which may explain different aggregation pathways of Afi Obtained models are composed of outer and core chains, and therefore, are significantly different than the structure of mature fibrils The interactions with water are the reason why the tetramer A/31-421 is more compact and less dry inside than fibrils Physicochemi­ cal properties of the proposed all-atom structures are in agreement with the available experimental observations and theoretical expectations Therefore, this dissertation provides possible models for further studies and design of higher order oligomers iv For A//1 42 trimcr, we performed extended all-atoms molecular dynamics simulations, both canonical and replica-exchange, of A//j 42 trimer starting from two different initial conformations: i) the pose produced by the best docking of a monomer aside of a dimer (simulation 1), representing oligomers freshly formed by assembling monomers; ii) a configuration extracted from an experimental mature fibril structure (simulation 2), representing settled oligomers in equilibrium with extended fibrils The results show that simulation of A//1 42 trimer populates regions consistent with small //-barrels, indicating the chance of spontaneous formation of domains resembling channel-like structures These structural domains are alternative to those more representative of mature fibrils (simulation 2), the latter showing a stable bundle of C-termini that is not sampled in simulation For the first time, the spontaneous existence of//-barrel structure in the results is observed from simulation works Moreover, trimer of A/?1 42 can form internal pores that are large enough to be accessed by water molecules and Ca2+ ions The effect of A/3[ 42 dodecamer and fibril on a multiple lipid types membrane, which is similar to that observed in AD patients, using all-atom molecular dynamics sim­ ulations Due to short simulation times, the formation of pores is not observed but, useful insight on the early events of this process has been obtained Namely, we showed that dodecamer distorts the lipid membrane to a greater extent than fibril, which may indicate that ion channels can be more easily formed in the presence of oligomers Based on this result we anticipate that oligomers are more toxic than mature fibrils, as observed experimentally Moreover, the Aj8-membrane interaction was found to be governed by the repulsive electrostatic interaction between A/? and ganglioside GM1 lipid We calculated the bending and compressibility modulus of the membrane in the absence of A/? and obtained good agreement with experiment We predict that the A/? [-42 dodecamer will increase the compressibility modulus, but has little effect on the bending modulus Due to the weak interaction with the membrane, A//1-42 mature fibrils insignificantly change the membrane elastic properties The results for A/?1 42 tetramer, triiner and dodecamer indicate that the used sim­ ulation methods are reasonable to study the structure and interaction between A/?1 42 oligomer and neuronal membrane These oligomers are disordered which is consis­ tent with experimental data Based on physicochemical properties of A/3[ 42 tetramer and trimer, the author proposed a hypothesis about the structural difference between oligomer and mature fibril Although the interaction between A//] 42 dodecamer, fibril and membrane is captured at the early events, but the molecular mechanism shed some lights on the role of neural toxicity of oligomerization Nguyễn Hoàng Linh V LỜI CẢM ƠN Lời nói đầu tiên, tơi xin chân thành cảm ơn GS.TSKH Mai Xn Lý Thầy dìu dắt tơi từ ngày đầu làm khoa học Tôi học nhiều điều từ thầy ngồi kiến thức chun mơn ỉ •J Tói xin cảm ơn PGS.TS Huỳnh Quang Linh tạo điều kiện đổ tơi hồn thành luận án Thầy chia sẻ cho lời khuyên chân thành, thiết thực gặp khó khăn Tôi chân thành cảm ơn quý Thầy (Cô) khoa Khoa khoa học ứng dụng Trường Đại học Bách Khoa, ĐHQG HCM giảng dạy thời gian làm nghiên cứu sinh Xin cảm ơn Thầy (Cơ) phịng Sau Đại học Trường Đại học Bách Khoa HCM hỗ trợ tơi hồn thành q trình học nghiên cứu Tơi xin cảm ơn gia đình, họ động lực cho tiến bước Tôi earn ơn anh Nguyễn Quốc Thái, thành viên thuộc nhóm nghiên cứu GS.TSKH Mai Xuân Lý hỗ trợ, thảo luận nhiều ý tưởng khoa học với Tôi xin cảm ơn anh Mai Văn Thanh lầm, Phạm Minh Trí, Phan Toại Tuyn giúp đỡ, chia sẻ khó khăn sống Tơi xin cảm ơn Tập đồn Vingroup Cơng ty CP hỗ trợ bới Chương trình học bổng thạc sĩ, tiến sĩ nước Quỹ Đổi sáng tạo Vingroup (VINIF), Viện Nghiên cứu Dữ liệu lớn Tôi xin cảm ơn quý thầy, cô thuộc hội đồng đánh giá luận án cấp đưa nhận xét, góp ý chân thành để tơi hồn thiện luận án Cuối cùng, tơi xin chân thành cảm ơn quý cựu đồng nghiệp Viện Khoa học Cơng nghệ Tính tốn hỗ trợ đổ tơi có thổ thực nghiên cứu Nguyễn Hoàng Linh vi MỤC LỤC ỊDanh sách hình VC xiv Danh sách bảng số liệu xvi 4» Danh sách tử viêt tăt xvii -GIỚI THIỆU ỉ - 8 10 12 Cơ SỞ LÝ THUYẾT VÀ PHƯƠNG PHÁP NGHIÊN cúul vii 15 15 15 16 16 16 17 17 17 17 18 18 19 19 19 19 20 21 mơ phịng protein 3.3 Các phương pháp mơ phóng 3.3.1 Mơ phóng docking 3.3.1.1 Khái niệm 3.3.1.2 Các thành phắn mơ phóng docking! 3.3.1.3 ứng diuig cửa mơ phóng docking 3.3.2 Mô động lực học phân tử (MD) 3.3.2.1 Khái niệm 3.3.2.2 Thuật toán MD 3.3.2.3 Các tập hợp thống kê 3.3.2.4 Tích phân phương trình chuyển động 3.3.2.5 Chọn điêu kiện ban đâu| 3.3.2.6 Cân nhiệt độ áp suất 3.3.2.7 Các ràng buộc holonomic 3.3.2.8 Diêu kiện biên tuán hồn 3.3.2.Ọ Phương pháp tính tương tác phi liên kết 3.3.2.10 Thuật toán Lưới-hạt Ewald (PME, Particle-mesh Ewald) 3.3.3 Phương pháp Trao đôi (RE Replica exchange) ■ 3.4 Các thiẽt lập mơ phóng phương pháp phản tích luận án 3.4.1 Sơ dồ thiết kế nghiên cứu 3.4.2 Cấu trúc tính chất hố lý trimer A/T12 3.4.2.1 Mơ phóng Động lực học phân tử kết hợp trao đôi (REMD, Replica exchange Molecular dynamics) 3.4.2.2 Phân tích liệu 3.4.3 Cấu trúc tính chất, hố lý tetramer A/?i-42 3.4.3.1 Các cấu trúc ban đầul 3.4.3.2 MÔ |REMD| • ■ • 3.4.3.3 Phương pháp phân tích biểu đồ có trọng số (WHAM, Weighted Histogram Analysis Method) 3.4.3.4 Mô phông động lực học phân tử (MD) tất nguyên tử _ 3.4.3.Õ Các cơng cụ phân tích liệu 3.4.4 Tương tác dodecamer, sợi A/?1 42 màng tế bào thần kinh 3.4.4.1 Các cấu trúc ban dầul 3.4.4.2 Mơ hình màng tế bào thần kinh 3.4.4.3 Mô dộng lực học phân tư| 3.4.4.4 Phân tích liệul _ • KÊT QUẢ VÀ THÁO LUẬnỊ 4.1 GIÓI THIỆU CHUNG vỀ KẾT qŨa| 4.2 24 24 24 24 24 26 26 26 27 27 28 30 31 32 35 36 38 39 41 41 42 42 43 44 44 44 45 46 47 49 49 50 52 52 54 NGHIÊN cứu VÊ CÀU TRÚC VÀ TÍNH CHAT HỐ LÝ cú A TR1MER A/?l 42 4.2.1 Sự khác biệt cấu trúc ban dầu Nguyễn Hoảng Linh viii 55 55 PHỤ LỤC RightsLink Printable License 10/11/22, 4:38 PM Portion fl g u res/t a b les/i 11 u st t i on s Number of figures/tables/i lustrations Format both print and electronic Are you the author of this Elsevier article? 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