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Computational Procedure for Predicting Excipient Effects on Protein–Protein Affinities
Open accessPublished version of a preprint
Abstract
Protein-protein interactions lie at the center of many biological processes and are a challenge in formulating biological drugs, such as antibodies. A key to mitigating protein association is to use small-molecule additives, i.e., excipients that can weaken protein-protein interactions. Here, we develop a computationally efficient model for predicting the viscosity-reducing effect of different excipient molecules by combining atomic-resolution MD simulations, binding polynomials, and a thermodynamic perturbation theory. In a proof of principle, this method successfully ranks the order of four types of excipients known to reduce the viscosity of solutions of a particular monoclonal antibody. This approach appears useful for predicting the effects of excipients on protein association and phase separation, as well as the effects of buffers on protein solutions.
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Cites
Highly accurate protein structure prediction with AlphaFold
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Metadata
- Authors
- Dignon, G. L., & Dill, K. A.
- Affiliations
- Stony Brook University (US)
- Corresponding author
- Dill, Ken A.
- Venue
- Journal of Chemical Theory and Computation
- Publisher
- American Chemical Society (ACS)
- Published
- 2024-01-31
- Volume
- 20
- Issue
- 3
- Pages
- 1479-1488
- ISSN
- 1549-9618 (ISSN-L)
- 1549-9626
- PMC
- PMC10868583
- OpenAlex
- W4391404684
- Cited by
- 5
- References
- 1
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1
- FWCI
- 0.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Chemical Theory and Computation (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute of General Medical Sciences (3RM1GM13513604S1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › Phase Equilibria and Thermodynamics
- Keywords
- protein-protein interaction, pharmaceutical excipients, viscosity reduction, monoclonal antibodies, thermodynamic perturbation theory, molecular dynamics simulation, protein association, phase separation, buffering effect, biopharmaceutical formulation
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