Deciphering GB1’s Single Mutational Landscape: Insights from MuMi Analysis
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Abstract
Mutational changes that affect the binding of the C2 fragment of Streptococcal protein G (GB1) to the Fc domain of human IgG (IgG-Fc) have been extensively studied using deep mutational scanning (DMS), and the binding affinity of all single mutations has been measured experimentally in the literature. To investigate the underlying molecular basis, we perform in silico mutational scanning for all possible single mutations, along with 2 μs-long molecular dynamics (WT-MD) of the wild-type (WT) GB1 in both unbound and IgG-Fc bound forms. We compute the hydrogen bonds between GB1 and IgG-Fc in WT-MD to identify the dominant hydrogen bonds for binding, which we then assess in conformations produced by Mutation and Minimization (MuMi) to explain the fitness landscape of GB1 and IgG-Fc binding. Furthermore, we analyze MuMi and WT-MD to investigate the dynamics of binding, focusing on the relative solvent accessibility of residues and the probability of residues being located at the binding interface. With these analyses, we explain the interactions between GB1 and IgG-Fc and display the structural features of binding. In sum, our findings highlight the potential of MuMi as a reliable and computationally efficient tool for predicting protein fitness landscapes, offering significant advantages over traditional methods. The methodologies and results presented in this study pave the way for improved predictive accuracy in protein stability and interaction studies, which are crucial for advancements in drug design and synthetic biology.
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- Authors
- Guclu, T. F., Atilgan, A. R., & Atilgan, C.
- Affiliations
- Sabancı Üniversitesi (TR)
- Faculty of Natural Sciences and Engineering, Sabanci University, Tuzla, Istanbul 34956, Turkey
- Corresponding author
- Guclu, Tandac F.
- Venue
- The Journal of Physical Chemistry B
- Publisher
- American Chemical Society (ACS)
- Published
- 2024-08-08
- Volume
- 128
- Issue
- 33
- Pages
- 7987-7996
- ISSN
- 1520-5207 (ISSN-L)
- 1520-6106
- PMC
- PMC11671028
- OpenAlex
- W4401425370
- Cited by
- 0
- References
- 59
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The Journal of Physical Chemistry B (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Sabanci University (acceptedVersion)
- Sabanci University (submittedVersion)
- Funders
- T?rkiye Bilimsel ve Teknolojik Arastirma Kurumu (121Z329, 122F149)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- streptococcal protein G, GB1, IgG Fc binding, deep mutational scanning, fitness landscape, hydrogen bonding, protein-protein binding, solvent accessibility, binding interface, protein stability, molecular dynamics
- MeSH terms
- Bacterial Proteins, Humans, Hydrogen Bonding, Immunoglobulin G, Immunoglobulin Fc Fragments, Mutation, Protein Binding, Molecular Dynamics Simulation
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