Dataset Information

Complementary Pocket and Network-Based Approach to Search for Spike Protein Allosteric Pocket Sites.

ABSTRACT: COVID-19 is a persistent public health concern due to the emergence of more virulent and contagious variants resulting from mutations in the spike protein. The spike protein in newer variants, including Delta and Omicron, may be less sensitive to neutralizing antibodies and have a more favorable binding environment to the human ACE2 receptor. In the interest of identifying anti-COVID-19 allosteric drugs, a network-based approach based on coarse-grained molecular dynamics (CGMD) simulations, in complement to pocket-based analysis, is used to identify the possible allosteric pathways of the wild-type, Delta, and Omicron BA.1 spike proteins. Three pockets around 30 Å away from the spike-ACE2 interface are identified underneath the three receptor-binding domain (RBD) chains, which are potentially druggable due to favorable hydrophobicity and surface accessibility. Meanwhile, the network-based approach reveals intrinsic changes within the coupling between the three RBD chains, which could affect the overall communication between the spike-ACE2 interface active site and the three pockets, in particular between the stronger coupling between RBD_A and RBD_B for the wild type, versus the stronger coupling between RBD_A and RBD_C in Omicron BA.1. These results are to be used in subsequent drug discovery studies in targeting the spike protein allosterically as part of the search for COVID-19 drugs and as part of the toolbox against future pandemics.

SUBMITTER: Cheng RL

PROVIDER: S-EPMC10701870 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Complementary Pocket and Network-Based Approach to Search for Spike Protein Allosteric Pocket Sites.

Cheng Ronny L RL Quirante Jerwin C JC Vargas Louise Erika Z LEZ Gatchalian Abigael F AF Nellas Ricky B RB

ACS omega 20231003 48

COVID-19 is a persistent public health concern due to the emergence of more virulent and contagious variants resulting from mutations in the spike protein. The spike protein in newer variants, including Delta and Omicron, may be less sensitive to neutralizing antibodies and have a more favorable binding environment to the human ACE2 receptor. In the interest of identifying anti-COVID-19 allosteric drugs, a network-based approach based on coarse-grained molecular dynamics (CGMD) simulations, in c ...[more]

PMID: 38075758

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Project description:BackgroundRecently, a number of large-scale cancer genome sequencing projects have generated a large volume of somatic mutations; however, identifying the functional consequences and roles of somatic mutations in tumorigenesis remains a major challenge. Researchers have identified that protein pocket regions play critical roles in the interaction of proteins with small molecules, enzymes, and nucleic acid. As such, investigating the features of somatic mutations in protein pocket regions provides a promising approach to identifying new genotype-phenotype relationships in cancer.MethodsIn this study, we developed a protein pocket-based computational approach to uncover the functional consequences of somatic mutations in cancer. We mapped 1.2 million somatic mutations across 36 cancer types from the COSMIC database and The Cancer Genome Atlas (TCGA) onto the protein pocket regions of over 5,000 protein three-dimensional structures. We further integrated cancer cell line mutation profiles and drug pharmacological data from the Cancer Cell Line Encyclopedia (CCLE) onto protein pocket regions in order to identify putative biomarkers for anticancer drug responses.ResultsWe found that genes harboring protein pocket somatic mutations were significantly enriched in cancer driver genes. Furthermore, genes harboring pocket somatic mutations tended to be highly co-expressed in a co-expressed protein interaction network. Using a statistical framework, we identified four putative cancer genes (RWDD1, NCF1, PLEK, and VAV3), whose expression profiles were associated with overall poor survival rates in melanoma, lung, or colorectal cancer patients. Finally, genes harboring protein pocket mutations were more likely to be drug-sensitive or drug-resistant. In a case study, we illustrated that the BAX gene was associated with the sensitivity of three anticancer drugs (midostaurin, vinorelbine, and tipifarnib).ConclusionsThis study provides novel insights into the functional consequences of somatic mutations during tumorigenesis and for anticancer drug responses. The computational approach used might be beneficial to the study of somatic mutations in the era of cancer precision medicine.

Dataset Information

Complementary Pocket and Network-Based Approach to Search for Spike Protein Allosteric Pocket Sites.

Publications

Complementary Pocket and Network-Based Approach to Search for Spike Protein Allosteric Pocket Sites.

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