# A multiscale model for binding kinetics of membrane receptors on cell surfaces

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $329,825

## Abstract

Project Summary
Membrane receptors on cell surfaces constitute around 60% of approved drug targets on the
pharmaceutical market. In most cases, they bind to extracellular ligands and initiate various intracellular
signaling pathways.  This process underlies many cellular activities such as adhesion and apoptosis.
Recent studies further showed that specificity of receptors binding can be modulated by synthesizing
chimeric ligands that artificially conjugate different subunits of molecular ligands together. This provides a
promising strategy to improve the efficiency and selectivity of drug-based therapies. However, our
understanding to the cellular functions of membrane receptors is largely limited by the fact that in vivo
binding of receptors has only been successfully measured in a very small number of cases. Most
methods isolate receptors and ligands from their biological surrounding in order to permit a more
convenient analysis. In living cells, receptors are anchored on surfaces of plasma membrane. The
membrane confinement significantly affects binding kinetics of receptors. Moreover, binding can also be
regulated by the flexibility and multivalency of chimeric ligands. These multi-level complexities lead to the
difficulty in quantifying binding kinetics of membrane receptors on cell surfaces. Computational modeling
can reach dimensions that are currently unapproachable in the laboratory. Thus, the objective of this
proposal is to build integrative models at different scales for studying the binding kinetics of cell surface
receptors with their extracellular protein ligands. We have developed different methods for simulating
protein binding kinetics on the molecular and lower-resolution levels. Through the application of these
methods to specific testing systems of T cell and costimulatory receptors, and the establishment of
ongoing experimental collaborations, we are specifically interested in answering the following two
questions: how does membrane confinement affect binding between receptors and ligands, and what
are the functional roles of multivalent ligands in regulating receptor binding. Using the information
derived from these two aspects of studies, we will further construct a multiscale modeling framework
to quantitatively calculate the kinetics of binding between multivalent ligands and multiple receptors
on cell surfaces. Our long-term goal is to practically design multivalent ligands for specific membrane
receptors so that cell signaling can be artificially modulated. In summary, this study will sheds light on
both basic mechanisms of ligand-receptor interactions and design principles of new drug candidates.
Moreover, the multiscale model can be applied to specific membrane receptor systems.

## Key facts

- **NIH application ID:** 10004665
- **Project number:** 5R01GM120238-06
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Yinghao Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $329,825
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004665

## Citation

> US National Institutes of Health, RePORTER application 10004665, A multiscale model for binding kinetics of membrane receptors on cell surfaces (5R01GM120238-06). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10004665. Licensed CC0.

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