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Unraveling the Stability of Plasma Proteins upon Interaction of Synthesized Androstenedione and Its Derivatives-A Biophysical and Computational Approach.

ABSTRACT: 4-Androstene-3-17-dione (4A), also known as androstenedione, is the key intermediate of steroid metabolism. 5?-Androstane-3-17-dione (5A) and (+)-6-methyl-5?-androstane-3-17-dione (6M) are the steroid derivatives of androstenedione. The interactions of androstenedione and its derivatives with plasma proteins are important in understanding the distribution and bioavailability of these molecules. In our present study, we have studied the binding affinity of androstenedione and its derivatives with plasma proteins such as human serum albumin (HSA) and ?1-acid glycoprotein (AGP). Our results showed that the 4A, 5A, and 6M steroid molecules can form stable complexes with HSA and AGP. The affinity of the studied steroid molecules with HSA is high compared to that with AGP, and the binding constants obtained for 4A, 5A, and 6M with HSA are 5.3 ± 2 × 104, 5.3 ± 1 × 104, and 9.5 ± 0.2 × 104 M-1, respectively. Further, binding sites of these steroid molecules in HSA are identified using molecular displacement and docking studies: it is found that 4A and 5A bind to domain III while 6M binds to domain II of HSA. Furthermore, the circular dichroism data revealed that there is a partial unfolding of the protein while interacting with androstenedione and its derivatives. Also, molecular dynamics simulations were carried out for HSA-androstenedione and its derivative complexes to understand their stability; hence, these results yielded that HSA-androstenedione and its derivative complexes were stabilized after 15 ns and maintained their stable structures.

SUBMITTER: Nerusu A

PROVIDER: S-EPMC6045264 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Unraveling the Stability of Plasma Proteins upon Interaction of Synthesized Androstenedione and Its Derivatives-A Biophysical and Computational Approach.

Nerusu Aparna A Reddy P Srinivasa PS Ramachary Dhevalapally B DB Subramanyam Rajagopal R

ACS omega 20171009 10

4-Androstene-3-17-dione (4A), also known as androstenedione, is the key intermediate of steroid metabolism. 5β-Androstane-3-17-dione (5A) and (+)-6-methyl-5β-androstane-3-17-dione (6M) are the steroid derivatives of androstenedione. The interactions of androstenedione and its derivatives with plasma proteins are important in understanding the distribution and bioavailability of these molecules. In our present study, we have studied the binding affinity of androstenedione and its derivatives with ...[more]

PMID: 30023521

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Project description:At the center of the SARS-CoV2 infection, the spike protein and its interaction with the human receptor ACE2 play a central role in the molecular machinery of SARS-CoV2 infection of human cells. Vaccine therapies are a valuable barrier to the worst effects of the virus and to its diffusion, but the need of purposed drugs is emerging as a core target of the fight against COVID19. In this respect, the repurposing of drugs has already led to discovery of drugs thought to reduce the effects of the cytokine storm, but still a drug targeting the spike protein, in the infection stage, is missing. In this work, we present a multifaceted computational approach strongly grounded on a biophysical modeling of biological systems, so to disclose the interaction of the SARS-CoV2 spike protein with ACE2 with a special focus to an allosteric regulation of the spike-ACE2 interaction. Our approach includes the following methodologies: Protein Contact Networks and Network Clustering, Targeted Molecular Dynamics, Elastic Network Modeling, Perturbation Response Scanning, and a computational analysis of energy flow and SEPAS as a protein-softness and monomer-based affinity predictor. We applied this approach to free (closed and open) states of spike protein and spike-ACE2 complexes. Eventually, we analyzed the interactions of free and bound forms of spike with hepcidin (HPC), the major hormone in iron regulation, recently addressed as a central player in the COVID19 pathogenesis, with a special emphasis to the most severe outcomes. Our results demonstrate that, compared with closed and open states, the spike protein in the ACE2-bound state shows higher allosteric potential. The correspondence between hinge sites and the Allosteric Modulation Region (AMR) in the S-ACE complex suggests a molecular basis for hepcidin involvement in COVID19 pathogenesis. We verify the importance of AMR in different states of spike and then study its interactions with HPC and the consequence of the HPC-AMR interaction on spike dynamics and its affinity for ACE2. We propose two complementary mechanisms for HPC effects on spike of SARS-CoV-2; (a) HPC acts as a competitive inhibitor when spike is in a preinfection state (open and with no ACE2), (b) the HPC-AMR interaction pushes the spike structure into the safer closed state. These findings need clear molecular in vivo verification beside clinical observations.

Dataset Information

Unraveling the Stability of Plasma Proteins upon Interaction of Synthesized Androstenedione and Its Derivatives-A Biophysical and Computational Approach.

Publications

Unraveling the Stability of Plasma Proteins upon Interaction of Synthesized Androstenedione and Its Derivatives-A Biophysical and Computational Approach.

Similar Datasets

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