Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics

By Gongpu Zhao, J. Perilla, Ernest L. Yufenyuy, Xin Meng, J. Ning, Jinwoo Ahn, A. Gronenborn, Klaus Schulten, C. Aiken, Peijun Zhang. Nature, 2013

819 citations recorded by the source corpus.

Retroviral capsid proteins are conserved structurally but assemble into different morphologies. The mature human immunodeficiency virus-1 (HIV-1) capsid is best described by a ‘fullerene cone’ model, in which hexamers of the capsid protein are linked to form a hexagonal surface lattice that is closed by incorporating 12 capsid-protein pentamers. HIV-1 capsid protein contains an amino-terminal domain (NTD) comprising seven α-helices and a β-hairpin, a carboxy-terminal domain (CTD) comprising four α-helices, and a flexible linker with a 310-helix connecting the two structural domains. Structures of the capsid-protein assembly units have been determined by X-ray crystallography; however, structural information regarding the assembled capsid and the contacts between the assembly units is incomplete. Here we report the cryo-electron microscopy structure of a tubular HIV-1 capsid-protein assembly at 8 Å resolution and the three-dimensional structure of a native HIV-1 core by cryo-electron tomography. The structure of the tubular assembly shows, at the three-fold interface, a three-helix bundle with critical hydrophobic interactions. Mutagenesis studies confirm that hydrophobic residues in the centre of the three-helix bundle are crucial for capsid assembly and stability, and for viral infectivity. The cryo-electron-microscopy structures enable modelling by large-scale molecular dynamics simulation, resulting in all-atom models for the hexamer-of-hexamer and pentamer-of-hexamer elements as well as for the entire capsid. Incorporation of pentamers results in closer trimer contacts and induces acute surface curvature. The complete atomic HIV-1 capsid model provides a platform for further studies of capsid function and for targeted pharmacological intervention.

Subfields: Ecology, Molecular Biology, Virology

View Paper: https://www.semanticscholar.org/paper/4d8807de5fdd4bbf311a8d8e356cd768020ea566

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Ecology

In Molecular Biology

Citations in the corpus

A new ensemble coevolution system for detecting HIV-1 protein coevolution (2015, methodology): “These helices near the capsid intra-and inter-subunit interaction interfaces play a key role in the capsid assembly and stability [1,79-81].”
Single-Particle Cryo-EM at Crystallographic Resolution. (2015, methodology): “Crystal structures of domains and fragments or sequence-based homology models were then fitted into the cryo-EM density maps by molecular dynamic simulations or other computational methods (DiMaio et al., 2015; Seidelt et al., 2009; Trabuco et al., 2009; Zhao et al., 2013).”
Weighted Ensemble Simulation: Review of Methodology, Applications, and Software (2017, neutral): “In addition to record-setting molecular dynamics (MD) simulations in terms of both length (57) and system size (71), it has become routine to carry out simulations on the microsecond timescale, a critical regime for biological processes such as protein conformational changes and binding processes.”
Anton 2: Raising the Bar for Performance and Programmability in a Special-Purpose Molecular Dynamics Supercomputer (2014, background): “…several based on millisecond-scale all-atom MD simulations [32, 37, 38, 46, 47]—have led to a number of scientific discoveries (e.g., [4, 8, 16, 23, 30, 35, 49, 55]) involving biological phenomena that were previously inaccessible to both computational and experimental investigation.”
An Atomistic Fingerprint Algorithm for Learning Ab Initio Molecular Force Fields (2017, background): “Molecular Dynamics (MD) simulations have been widely used for studying atomistic systems, e.g. proteins and catalysts, due to their ability to precisely capture transient events and to predict macroscopic properties from microscopic details [1,2].”
Many-Body Coarse-Grained Interactions Using Gaussian Approximation Potentials. (2016, background): “On general-purpose high-performance computing clusters, one of the largest all-atom MD simulations to date was of the HIV-1 capsid [11], with 64 million atoms in the solvated system.”
MMTF—An efficient file format for the transmission, visualization, and analysis of macromolecular structures (2017, methodology): “Using the NGL viewer [20] and MMTF, the currently largest structure in the PDB, the HIV viral capsid (PDB ID 3J3Q) [2], can now be visualized on a mobile device (Fig 1A).”
Protein Modelling: What Happened to the “Protein Structure Gap”? (2013, neutral): “In this context, cryo-electron microscopy techniques play a central role for determining the molecular architecture of large macromolecular complexes (Lasker et al., 2012b; Velazquez-Muriel et al., 2012; Zhao et al., 2013).”
Guidelines for the analysis of free energy calculations (2015, background): “Models seek to mimic or simulate the processes in question, helping reveal and provide new understanding of mechanisms and phenomena which might be challenging or impossible to probe experimentally [20, 23, 38, 43].”