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Tumor Discovery Bioinformatics insights into CCL2 mutations

analysis revealed distinct fluctuation patterns in the mutant Computational methods are essential in providing
protein compared to the native structure, indicating that the foundation for genetic research and enabling the
the mutation significantly impacted protein stability and understanding of the molecular basis of diseases.
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dynamics (Figure 4B). The analysis showed a substantial Moreover, computational methods play a crucial role
increase in residue-level variation in the mutant protein, in identifying disease-causing mutations and exploring
suggesting that the mutation caused notable changes in the potential therapeutic strategies. 102,103 These methods also
protein’s conformation and increased its flexibility. aid in the clinical assessment of genetic variants, enabling
Analysis of the intramolecular hydrogen bonds in the more informed and effective treatment decisions.
CCL2 protein revealed a notable decrease in the number of 5. Conclusion
hydrogen bonds formed in the mutant protein compared to
the native structure during the simulation. This reduction This investigation into the oncogenic missense mutations
suggests an increase in the flexibility of the mutant of CCL2, particularly the C59G mutation, revealed that this
protein and significant structural differences between the specific mutation may impair CCL2 activity, potentially
two forms (Figure 5A and B). To elucidate the structural lower the risk of cancer, and enhance the immune response.
dynamics of the native and mutant CCL2 proteins, an Through bioinformatics and computational analyses, we
ED analysis was performed. This approach enabled the found that the C59G mutation significantly affects the
identification of correlated movements within both stability and function of CCL2, potentially hindering its
protein structures, providing insights into the molecular interaction with the CCR2 receptor. This mutation, one of
mechanisms underlying their functional differences. the 83 CCL2 missense mutations, is associated with disease
Examination of the sum of the eigenvalues revealed that causation and has implications for cancer development.
the primary fluctuations were confined to the first two MD simulations and structural analyses confirmed that
eigenvectors for both the native and mutant proteins. This these mutations induce substantial conformational changes,
finding suggests that these PCs capture the main motions decrease stability, and alter the ED. Despite the increased
within the system (Figure 5C and D). binding affinities of mutant CCL2 to CCR2, the C59G
mutation markedly affects the protein’s stability and function.
Analysis of the Rg plot indicated that the amino
acid substitution at position G59 had a destabilizing This study emphasizes the importance of understanding the
molecular characteristics of CCL2 mutations, particularly
effect on the protein’s structure, which led to reduced
protein compactness (Figure 6A and B). This finding was C59G, in influencing disease processes, such as that of
supported by SASA analysis, which revealed higher SASA colorectal cancer, and highlights the potential implications
values for the mutant protein, indicating a substantial for immune responses and cancer regulation.
structural transition (Figure 6C and D). The observed Acknowledgments
conformational changes strongly suggest that the amino
acid substitution in the mutant protein significantly altered None.
its overall structure. Furthermore, the mutation resulted
in a less stable, more flexible, and less compact structure Funding
compared to the native protein. Our results collectively This work was supported by National Natural Science
indicate that the mutation had a profound impact on Foundation of China (32270438, 32170498, 31970388), the
protein structure and stability. National Key Research and Development Program of China
Previous studies have shown the synergistic value (2021YFF0702000, 2018YFD0900602), 1.3+.5 project for
of combining in silico approaches and wet laboratory disciplines of excellence, West China Hospital, Sichuan
experiments to gain a comprehensive understanding University (ZYJC21050), the Science and Technology
of biological processes. 97,98 The combination of Department of Sichuan Province (2022YFH0116), the
computational methods and experimental techniques Priority Academic Program Development of Jiangsu
has emerged as a potent strategy for predicting and Higher Education Institutions (PAPD), the National
confirming hypotheses across various biological systems. Clinical Research Center for Geriatrics, West China
98
Integrating computational mutation predictions with Hospital, and Sichuan University (Z2023JC003).
MD simulation analysis has been pivotal in pinpointing Conflict of interest
disease-causing mutations. This approach has allowed
99
for the identification of the most harmful mutations from Mohammad Amjad Kamal is the Guest Editor of this
a large pool of mutations, offering valuable insights into special issue, but was not in any way involved in the
the molecular mechanisms underlying various diseases. editorial and peer-review process conducted for this paper,
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Volume 3 Issue 4 (2024) 21 doi: 10.36922/td.3891