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Probing Amyloid Fibril Self-Assembly with Network Hamiltonian Simulations in Explicit Space

Award Number: R16GM150706
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/16/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Probing Amyloid Fibril Self-Assembly with Network Hamiltonian Simulations in Explicit Space - Project Summary/Abstract Amyloid fibril formation is central to the disease etiology of a number of human diseases, including Alzheimer’s disease, type 2 diabetes, and a variety of prion diseases. Although molecular structures for thousands of amyloid fibrils have been resolved using techniques like X-ray crystallography and nuclear magnetic resonance (NMR), the mechanism of amyloid fibril formation is largely unknown. The mechanism of primary nucleation, whereby fibril formation begins in a solvent environment that previously did not contain any amyloid fibrils, a crucial step in amyloid disease onset, is particularly mysterious. Dye-binding fluorescence microscopy experiments have been used to observe the spontaneous formation fibril formation in microfluidic chambers from individual primary nucleation sites. These experiments revealed two key mechanistic details: 1) fibril formation propagated through solution as a traveling wave of constant velocity moving away from the primary nucleation site, and 2) there exists a linear relationship between the lag time before fibril formation and the inverse of volume. We hypothesize that the confinement of insulin to smaller volumes is an evolutionary adaptation that renders amyloid fibril formation prohibitively slow, in turn, influencing the size of insulin granules in pancreatic beta cells. We will develop novel top-down coarse-grained model that utilize a bridged approach, whereby two representations of an ensemble of fibril-forming proteins (one purely topological network representation and one granular representation in explicit space) exchange information as time evolves. This approach will leverage the high computational efficiency of exponential-family random graph models (purely topological), with improved spatial realism provided by a minimal explicit space model based on a Lennard-Jones fluid. The models will first be fit using a threefold validation strategy whereby they will be parameterized to simultaneously reproduce three known experimental observables: the fibril’s topological structure (derived from structures reported in the protein data bank), fibril growth kinetics (compared to dye- binding fluorescence experiments), and the spatial propagation patterns of fibril formation (compared to aforementioned microfluidic experiments). Analysis of the validated models will then be used to propose potential mechanisms for primary nucleation, the modulation of which is actively being explored for the development of preventative treatments for amyloid diseases. The proposed work will require an innovation to the network Hamiltonian methodology (first introduced by the PI and others), in that it will be the first to include explicit spatial degrees of freedom. This development will facilitate the comparison of network Hamiltonian models to experimental results and enhance the predictive power of the simulations, for both the present work and future studies in molecular self-assembly.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $183,125 )
2025	2025	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 N 4TH ST FL 4	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	7/22/2025	NON-COMPETING CONTINUATION	$183,125
														Subtotal = $183,125

Issue Date FY: 2024 ( Subtotal = $178,937 )
2024	2024	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 N 4TH ST FL 4	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	7/4/2024	NON-COMPETING CONTINUATION	$178,937
														Subtotal = $178,937

Issue Date FY: 2023 ( Subtotal = $168,818 )
2023	2023	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 4TH ST 3RD FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	8/16/2023	NEW	$168,818
														Subtotal = $168,818

Grand Total All Awards = $530,880

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Probing Amyloid Fibril Self-Assembly with Network Hamiltonian Simulations in Explicit Space

Award Number: R16GM150706

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/16/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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