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Decoding membrane protein folding and functional principles using simple designed building blocks

Award Number: R35GM166357
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: 07/20/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Decoding membrane protein folding and functional principles using simple designed building blocks - This research program integrates protein design with biophysical experiments to create new routes for clarifying the fundamental chemical rules and sequence-structure relationships underlying how proteins interact in lipid. Membrane proteins are the targets of most drugs, but can be complex, dynamic, unstable, and difficult to study. The ability to unveil molecular mechanisms and develop new medicines have long been limited by knowledge and technical gaps in how we interpret, predictively model, and chemically perturb these protein’s behaviors in heterogenous lipid environments. The principal problem is the poor current delineation of sequence elements and understanding of energetics that govern transmembrane (TM) spans interaction modes, which diverge from those in water. To improve general scientists’ capacity to comprehend and manipulate membrane proteins towards improving human health, we aim to develop novel strategies for illuminating generalizable “first principles” alongside software describing how stability, selectivity, and function can be encoded in TM spans. Our R35 program, unified by this theme, pursues 3 distinct directions via a common approach: building synthetic membrane proteins as simplified model molecules for unprecedent access to test data-driven hypotheses for how TM regions assemble and shape their lipid surroundings. The 1st project capitalizes on the known but underexplored paradigm that there are only a few ways that membrane domains pack their TM helices, forming a basis set of core TM helix geometries reused across all protein folds. We hypothesize that defining the sequence patterns and molecular features encoding these fundamental “TM building blocks” will establish biophysical rules explaining most protein interactions in lipid – like a playbook for membrane protein behavior. To do so, we are designing synthetic TM proteins representing the sequence scope of each TM building block, tested by folding assays to uncover which features indeed encode stability and specificity, thus defining “consensus” elements of each motif. By revealing new previously cryptic molecular patterns and general folding principles, these studies will transform the field’s ability to identify the key structurally stabilizing elements in natural membrane proteins and interpret how their subtle variations impact mechanism in disease. The 2nd direction will build generative protein models missing in the field encoding sequences and structures tailored for membrane environments, tools to guide basic science and unlock new biotechnologies. We hypothesize there is sufficient membrane protein sequence- structure data available and propose data structures suitable for training more advanced, comprehensive machine learning models – motivated by past design of stable TM complexes with simpler precursor methods. A platform for rapid expression and tests of folding support obtaining “ground-truth” experimental feedback to validate and improve models. The 3rd project tests if TM building blocks provide a facile framework to construct complex, functional multi-pass proteins. We focus on engineering protein scaffolds to enact phospholipid passive transport “scrambling” between bilayer leaflets, modelling this activity that regulates processes such as apoptosis, clotting, and tumor immunosuppression. By abstracting properties of natural transporters and insertases, we aim to define generalized mechanisms for how TM regions can manipulate their lipid surroundings to control local energy barriers, with implications to many cell functions mediated by membrane deformations.


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: 2026 ( Subtotal = $506,000 )
2026	2026	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	7/20/2026	NEW	$506,000
														Subtotal = $506,000

Grand Total All Awards = $506,000

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Decoding membrane protein folding and functional principles using simple designed building blocks

Award Number: R35GM166357

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: 07/20/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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