The conformational feasibility for the formation of reaching dimer in ASV and HIV integrase: a molecular dynamics study.
Retroviral integrases are reported to form alternate dimer assemblies like the core-core dimer and reaching dimer. The core-core dimer is stabilized predominantly by an extensive interface between two catalytic core domains. The reaching dimer is stabilized by N-terminal domains that reach to form intermolecular interfaces with the other subunit's core and C-terminal domains (CTD), as well as CTD-CTD interactions. In this study, molecular dynamics (MD), Brownian dynamics (BD) simulations, and free energy analyses, were performed to elucidate determinants for the stability of the reaching dimer forms of full-length Avian Sarcoma Virus (ASV) and Human Immunodeficiency Virus (HIV) IN, and to examine the role of the C-tails (the last ~16-18 residues at the C-termini) in their structural dynamics. The dynamics of an HIV reaching dimer derived from small angle X-ray scattering and protein crosslinking data, was compared with the dynamics of a core-core dimer model derived from combining the crystal structures of two-domain fragments. The results showed that the core domains in the ASV reaching dimer express free dynamics, whereas those in the HIV reaching dimer are highly stable. BD simulations suggest a higher rate of association for the HIV core-core dimer than the reaching dimer. The predicted stability of these dimers was therefore ranked in the following order: ASV reaching dimer < HIV reaching dimer < composite core-core dimer. Analyses of MD trajectories have suggested residues that are critical for intermolecular contacts in each reaching dimer. Tests of these predictions and insights gained from these analyses could reveal a potential pathway for the association and dissociation of full-length IN multimers.
a Centre for Bioinformatics, School of Life Sciences , Pondicherry University , Puducherry 605014 , India.
Sangeetha
http://orcid.org/0000-0002-4525-6152
S
Balasubramanian
a Centre for Bioinformatics, School of Life Sciences , Pondicherry University , Puducherry 605014 , India.
Muthukumaran
M
Rajagopalan
b Institute for Cancer Research , Fox Chase Cancer Center , Philadelphia , PA 19111 , USA.
Ravi Shankar
RS
Bojja
b Institute for Cancer Research , Fox Chase Cancer Center , Philadelphia , PA 19111 , USA.
Anna Marie
AM
Skalka
b Institute for Cancer Research , Fox Chase Cancer Center , Philadelphia , PA 19111 , USA.
Mark D
MD
Andrake
a Centre for Bioinformatics, School of Life Sciences , Pondicherry University , Puducherry 605014 , India.
Amutha
A
Ramaswamy
D020816:Amino Acid Motifs; D001358:Avian Sarcoma Viruses / Q000737:chemistry* / Q000201:enzymology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D019427:HIV Integrase / Q000737:chemistry*; D015497:HIV-1 / Q000737:chemistry* / Q000201:enzymology; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D013816:Thermodynamics
D019427:HIV Integrase
ASV; ASV – Avian Sarcoma Virus; CCD – Catalytic Core domain; CTD – C-terminal domain; DNA – deoxyribo nucleic acid; HIV; HIV – Human Immunodeficiency Virus; IN – Integrase; MMTV – Mouse Mammary Tumor Virus; NTD – N-terminal domain; PFV – Prototype Foamy Virus; RSV – Rous Sarcoma Virus; SAXS – small angle X-ray scattering; core–core dimer; integrase; reaching dimer