title: Structural Ensemble of CD4 Cytoplasmic Tail (402-419) Reveals a Nearly Flat Free-Energy Landscape with Local α-Helical Order in Aqueous Solution.
abstract: The human cluster determinant 4 (CD4), expressed primarily on the surface of T helper cells, serves as a coreceptor in T-cell receptor recognition of MHC II antigen complexes. Besides its cellular functions, CD4 serves as a primary receptor of human immunodeficiency virus (HIV) type 1. The cytoplasmic tail of CD4 (residues 402-419) is known to be involved in direct interaction with the HIV-1 proteins Vpu and Nef. These two viral accessory proteins (Vpu and Nef) downregulate CD4 in HIV-1 infected cells by multiple strategies and make the body susceptible to all forms of infections. In this work, we carried out extensive replica exchange molecular dynamics simulations in explicit water with three popular protein force fields Amber ff99SB, Amber ff99SB*-ILDN, and CHARMM36 to characterize the equilibrium conformational ensemble of CD4-tail (402-419) and further validated the simulated ensembles with known NMR data. We found that ff99SB*-ILDN gives a better description of the structural ensemble of this peptide compared with ff99SB and CHARMM36. The peptide adopts multiple distinct conformations with varying degree of residual secondary structures. In particular, we observed 28, 7, and 5% average α-helical, β-strand, and 3(10)-helix content, respectively, for ff99SB*-ILDN. The peptide chain shows the tendency of helix formation in a cooperative manner, seeding at residues 407-410, and subsequently extending toward both ends of the chain. Furthermore, we constructed Markov state model (MSM) from large-scale molecular dynamics simulations to study the dynamics of transitions between different metastable states explored by this peptide. The mean first passage times computed from MSM indicate rapid interconversion of these states, and the time scales of transitions range from several nanoseconds to hundreds of microseconds. Our results show good agreement with experimental data and could help to understand the key molecular mechanisms of T-cell activation and HIV-mediated receptor interference.
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research Bhopal , Bhopal By-pass Road, Bhauri, Bhopal 462066, Madhya Pradesh, India.
authors.forename: Navjeet
authors.initials: N
authors.lastname: Ahalawat
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research Bhopal , Bhopal By-pass Road, Bhauri, Bhopal 462066, Madhya Pradesh, India.
authors.forename: Simran
authors.initials: S
authors.lastname: Arora
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research Bhopal , Bhopal By-pass Road, Bhauri, Bhopal 462066, Madhya Pradesh, India.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Murarka
mesh_terms: D015704:CD4 Antigens / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D056004:Molecular Dynamics Simulation; D013601:T-Lymphocytes / Q000166:cytology; D014867:Water / Q000737:chemistry*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D054299:env Gene Products, Human Immunodeficiency Virus; D014867:Water