Presentation Title

Computational Analysis of Helical Interactions in Resistin

Faculty Mentor

Dimitrios Morikis

Start Date

18-11-2017 1:45 PM

End Date

18-11-2017 2:00 PM

Location

9-243

Session

Engineering/CS 1

Type of Presentation

Oral Talk

Subject Area

engineering_computer_science

Abstract

The endocrine system is responsible for regulating the functions of the human body but can sometimes undergo periods of dysregulation that lead to the development of endocrine metabolic disorders. The hormone resistin, known for its increased resistance to the effects of insulin, exists as a trimer in its natural form and is correlated with variances in endocrine response. In this study, computational structural analysis methods were used to evaluate the structure of resistin, primarily its N-terminal helices, not only in its trimer form but also in its monomer form to observe whether structural stability and possible binding interactions to putative receptors could be retained. Structural analysis was performed with the computational tool UCSF Chimera to visualize the various forms of resistin and to analyze physicochemical properties, such as hydrophobicity and polarity, that contribute to the stabilization of the structures. The physicochemical analysis involved the use of the webservers PDBePISA and PROPKA to investigate the intermolecular interactions between the helices of the trimer and to analyze the shifts of pKa values for ionizable amino acids involved in coulombic interactions, respectively. In addition, electrostatic analysis was completed with our lab’s computational framework AESOP to determine the electrostatic interactions between ionizable amino acids within the alpha-helices of the trimer that contribute to structural stability. The data obtained from the computational study demonstrated that resistin is stable in its trimer form and is also likely to be stable in its monomer form. Overall, a thorough understanding of the structural properties of resistin may provide further information of developing a biotherapeutic drug to target diseases of the endocrine system.

Summary of research results to be presented

The structural analysis of the study, which involved the use of the computational tool Chimera, primarily showed a well-defined structure a standalone helix of resistin due to amphipathicity from the presence of opposite hydrophobic and polar surfaces. Analysis of hydrogen bonds also showed that there were a total of 48 intramolecular hydrogen bonds for the standalone helices of Chains A, B, and C. In addition, the data obtained from the webserver PDBePISA showed that 6 intermolecular interactions, specifically 3 hydrogen bonds and 3 salt bridges, stabilized the trimer helices of resistin. Through the use of the webserver PROPKA, there were 20 ionizable amino acids from the standalone helix from chain B of resistin and from the helices of the trimer form of resistin that had differences greater than 0.5 units between their apparent and model pKa values and thus demonstrated their involvement in salt bridges and Coulombic interactions. Finally, the AESOP analysis demonstrated the importance of electrostatic interactions between the helices of the trimer form of resistin, evaluated through changes in electrostatic energies of association for five interfacial ionizable amino acids after they were mutated to alanine.

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Nov 18th, 1:45 PM Nov 18th, 2:00 PM

Computational Analysis of Helical Interactions in Resistin

9-243

The endocrine system is responsible for regulating the functions of the human body but can sometimes undergo periods of dysregulation that lead to the development of endocrine metabolic disorders. The hormone resistin, known for its increased resistance to the effects of insulin, exists as a trimer in its natural form and is correlated with variances in endocrine response. In this study, computational structural analysis methods were used to evaluate the structure of resistin, primarily its N-terminal helices, not only in its trimer form but also in its monomer form to observe whether structural stability and possible binding interactions to putative receptors could be retained. Structural analysis was performed with the computational tool UCSF Chimera to visualize the various forms of resistin and to analyze physicochemical properties, such as hydrophobicity and polarity, that contribute to the stabilization of the structures. The physicochemical analysis involved the use of the webservers PDBePISA and PROPKA to investigate the intermolecular interactions between the helices of the trimer and to analyze the shifts of pKa values for ionizable amino acids involved in coulombic interactions, respectively. In addition, electrostatic analysis was completed with our lab’s computational framework AESOP to determine the electrostatic interactions between ionizable amino acids within the alpha-helices of the trimer that contribute to structural stability. The data obtained from the computational study demonstrated that resistin is stable in its trimer form and is also likely to be stable in its monomer form. Overall, a thorough understanding of the structural properties of resistin may provide further information of developing a biotherapeutic drug to target diseases of the endocrine system.