Biology subjects

Perilla, J. R.

Publications and source records attributed to Perilla, J. R..

At least 19 recordsLinked to original sources

bioRxiv2026

MxB N-Terminus Adopts a Stable α-Helix to Engage the HIV-1 Capsid Trimer Interface

The HIV-1 capsid, composed of capsid (CA) proteins arranged into a conical surface lattice, serves as a critical platform for host-pathogen interactions. Many host cofactors regulate HIV-1 infection by selectively recognizing the higher-order CA lattice rather than individual monomers or capsomers. Among these, Myxovirus resistance protein B (MxB) is a key cellular restriction factor that binds the capsid via its N-terminal fragment containing an arginine-rich motif (RRR), blocking HIV-1 infection at early infection stages. However, the structural basis of this interaction has remained elusive. Here, we present a structural characterization of the CA lattice in complex with the MxB N-terminal fragment using cryo-electron tomography and subtomogram averaging. Combining cryoEM structures with EM-guided all-atom molecular dynamics simulations, we identify residue-specific interactions between MxB and the CA trimer interfaces. Notably, residues 10-20 of the MxB N-terminus adopt an alpha-helical conformation that stabilizes binding at the CA trimer interface, revealing a previously unrecognized mode of capsid engagement. These findings provide new insight into arginine-rich motif-mediated recognition by MxB and other host factors and establish a structural framework for the development of capsid-targeting antiviral therapeutics.

microbiology↗

bioRxiv2026

Lenacapavir prevents production of infectious HIV-1 by abrogating immature virus assembly.

The HIV-1 capsid effector Lenacapavir (LEN) acts by disrupting the early (reverse transcription and nuclear entry) and late (assembly and maturation) stages of the viral lifecycle. The early stage requires an intact Capsid consisting of a lattice of capsid protein (CA) hexamers and pentamers. Phenylalanine-Glycine (FG) containing nuclear pore proteins interact with Capsid hexamers at their FG pockets, facilitating nuclear entry. Disruption of Capsid lattice stability, or competitive binding to the FG pocket, by LEN blocks infection. Here, we provide insight into the effects of LEN on the late stage. Using a combination of cryo-EM structure determination, in vitro assembly, and in situ viral assays, we determined that treatment of producer cells with LEN abrogates the production of infectious virus via multiple mechanisms. Previous studies have shown that HIV-1 produced from LEN treated cells have improperly formed Capsids. However, how LEN interacts with the CA domain of the Gag polyprotein during assembly, prior to maturation, is unclear. Using a viral protease (PR) defective HIV-1 clone, which traps the Gag lattice in an immature state, we found that LEN dramatically remodulates the CA domain. The resulting CA layer was mature-like despite the absence of PR cleavage. We dubbed this unnatural state as "premature" lattice. Proper immature and mature lattice formation requires inositol hexakisphosphate (IP6), but our cryo-EM work revealed a lack of IP6 in the premature lattice. These findings provide insight into the mechanisms by which LEN prevents infectious HIV-1 production.

molecular biology↗

bioRxiv2026

Stoichiometric binding of Cyclophilin-A to the HIV-1 capsid modulates its mechanoelastic properties

HIV-1 nuclear entry requires a capsid that is sufficiently stable to protect and transport the viral genome yet sufficiently deformable to traverse the nuclear pore complex. Cyclophilin A (CypA), a host cell factor that binds the capsid in the cytoplasm, regulates early replication events; however, its effects on capsid mechanics remain unresolved. Here, we used atomic force microscopy nanoindentation simulations of CypA-decorated HIV-1 capsids across binding stoichiometries to characterize their mechanical response. The capsid exhibits curvature-dependent mechanical heterogeneity, with stiffness and transverse deformability varying along its surface. CypA binding progressively increased capsid brittleness, promoting structural failure at lower deformations. At high CypA:CA ratios, CypA binding overrides intrinsic sequence-dependent differences in ductility across wild-type and mutant capsids. These findings establish a direct link between CypA binding and capsid mechanoelastic properties, supporting a stoichiometry-dependent model in which balanced CypA binding preserves flexibility for nuclear entry, whereas excessive binding compromises nuclear import.

biophysics↗

bioRxiv2026

A Hybrid Gag Lattice as a Structural Intermediate in HIV-1 Maturation

HIV-1 maturation converts the spherical immature Gag lattice into the conical mature capsid required for infectivity, yet the structural route linking these two lattice endpoints remains unclear. Using single-particle cryo-electron microscopy and cryo-electron tomography on reconstituted assemblies and virus-like particles (VLPs), we identify a distinct hybrid lattice in which the capsid protein (CA) N-terminal domain adopts a mature-like conformation, whereas the CA C-terminal domain-SP1 layer remains immature. This architecture is observed in native, enveloped VLPs produced in human cells, demonstrating formation under physiologically relevant conditions. The hybrid lattice engages three myo-inositol hexakisphosphate (IP6) molecules per CA-SP1 hexamer, underscoring IP6-dependent stabilization; accordingly, excess IP6 enriches the hybrid population. Tomographic mapping shows that hybrid regions coexist with the immature lattice within the same particle and are enriched near lattice discontinuities, consistent with edge-localized remodeling that can accommodate conformational rearrangements and partial disassembly and reassembly. Disrupting a hybrid-specific inter-hexamer contact preserves immature lattice assembly and particle release but abrogates infectivity, compromises core integrity, and prevents mature lattice formation, implicating the hybrid architecture as an on-pathway intermediate. Molecular dynamics simulations further support coordinated rearrangements that bias the system away from the immature configuration toward hybrid and then mature organizations. Together, these results support a maturation model in which localized displacive remodeling and partial disassembly/reassembly act in concert, with IP6 tuning the balance among lattice states. This study provides new insight into HIV-1 maturation and identifies the hybrid lattice as a potential therapeutic target.

biochemistry↗

bioRxiv2025

A geometric criterion links HIV-1 capsid topography to its biophysical properties and function

Mathematical models of virus capsid structure are pillars of modern virology, aiding the understanding of viral mechanisms and the design of antiviral interventions. Traditionally, the HIV-1 capsid core geometry is represented as a fullerene lattice, akin to the icosahedral models of spherical viruses in Caspar-Klug theory. However, recent studies revealed that many viral capsids deviate from such idealised lattices, with important functional implication. Here we show that this is the case also for the conical HIV-1 core geometries, in which the hexamer and pentamer boundaries form a pseudo-tiling rather than a perfectly aligned fullerene network. We introduce a triangular geometric criterion that quantifies local deviations of an HIV-1 atomic model from its idealised fullerene backbone. Using this criterion, we present that this difference in geometric organisation between idealised (fullerene) and actual (data-derived) capsid model has implications for the capsids biophysical properties. We also discuss the use of the geometric criterion as a predictive tool regarding cofactor binding and implied geometric changes in the capsid surface coupled to the interfacial frustration response. Our results establish a quantitative framework linking capsid geometry, curvature, and biophysical function, offering new perspectives for assembly inhibitor design and lentiviral vector engineering.

bioinformatics↗

bioRxiv2025

In-cell Structure and Variability of Pyrenoid Rubisco

Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is a key enzyme in the global carbon cycle, catalyzing CO2 fixation during photosynthesis. To overcome Rubiscos inherent catalytic inefficiency, many photosynthetic organisms have evolved CO2-concentrating mechanisms. Central to these mechanisms is the pyrenoid, a protein-dense organelle within the chloroplast of eukaryotic algae, which increases the local concentration of CO2 around Rubisco and thereby enhances its catalytic efficiency. Although the structure of Rubisco has been extensively studied by in vitro methods such as X-ray crystallography and single particle cryo-EM, its native structure within the pyrenoid, its dynamics, and its association with binding partners remain elusive. Here, we investigate the structure of native pyrenoid Rubisco inside the green alga Chlamydomonas reinhardtii by applying cryo-electron tomography (cryo-ET) on cryo-focused ion beam (cryo-FIB) milled cells, followed by subtomogram averaging and 3D classification. Reconstruction at sub-nanometer resolution allowed accurate modeling and determination of a closed (activated) Rubisco conformation. Comparison to other reconstructed subsets revealed local variations at the complex active site and at the large subunit dimers interface, as well as association with binding proteins. The different structural subsets distribute stochastically within the pyrenoid. Taken together, these findings offer a comprehensive description of the structure, dynamics, and functional organization of Rubisco within the pyrenoid, providing valuable insights into its critical role in CO2 fixation.

cell biology↗

bioRxiv2025

Structural basis for HIV-1 capsid adaption to rescue IP6-packaging deficiency

Inositol hexakisphosphate (IP6) promotes HIV-1 assembly via its interaction with the immature Gag lattice, effectively enriching IP6 within virions. During particle maturation, the HIV-1 protease cleaves the Gag polyproteins comprising the immature Gag lattice, releasing IP6 from its original binding site and liberating the capsid (CA) domain of Gag. IP6 then promotes the assembly of mature CA protein into the capsid shell of the viral core, which is required for infection of new target cells. Recently, we reported HIV-1 Gag mutants that assemble virions independently of IP6. However, these mutants are non-infectious and unable to assemble stable capsids. Here, we identified a mutation in the C-terminus of CA - G225R - that restores capsid formation and infectivity to these IP6-packaging-deficient mutants. Furthermore, we show that G225R facilitates the in vitro assembly of purified CA into capsid-like particles (CLPs) at IP6 concentrations well below those required for WT CLP assembly. Using single-particle cryoEM, we solved structures of CA hexamer and hexameric lattice of mature CLPs harbouring the G225R mutation assembled in low-IP6 conditions. The high-resolution (2.7 [A]) cryoEM structure combined with molecular dynamics simulations of the G225R capsid revealed that the otherwise flexible and disordered C-terminus of CA becomes structured, extending to the pseudo two-fold hexamer-hexamer interface, thereby stabilizing the mature capsid. This work uncovers a structural mechanism by which HIV-1 adapts to a deficiency in IP6 packaging. Furthermore, the ability of G225R to promote mature capsid assembly in low-IP6 conditions provides a valuable tool for capsid-related studies and may indicate a heretofore unknown role for the unstructured C-terminus in HIV-1 capsid assembly.

microbiology↗

bioRxiv2024

Structural maturation of the matrix lattice is not required for HIV-1 particle infectivity

HIV-1 assembly is initiated by the binding of Gag polyproteins to the inner leaflet of the plasma membrane, mediated by the myristylated matrix (MA) domain of Gag. Subsequent to membrane binding, Gag oligomerizes and buds as an immature, non-infectious virus particle, which, upon cleavage of the Gag precursor by the viral protease, transforms into a mature, infectious virion. During maturation, the MA lattice underlying the viral membrane undergoes a structural rearrangement and the newly released capsid (CA) protein forms a mature capsid that encloses the viral genome. While it is well established that formation of the mature capsid is essential to particle infectivity, the functional role of MA structural maturation remains unclear. Here, we examine MA maturation of an MA triple mutant, L20K/E73K/A82T, which exhibits distinct biochemical behaviours. The L20K/E73K/A82T mutant is a revertant derived by propagating the L20K mutant, which exhibits reduced infectivity and increased association of the Gag polyprotein with membranes. L20K/E73K/A82T replicates similarly to wild type but retains the increased Gag membrane binding properties of L20K. L20K/E73K/A82T MA also sediments to high-density fractions in sucrose gradients after detergent treatment under conditions that fully solubilize WT MA, suggesting enhanced MA-MA interactions. Cryo-electron tomography with subtomogram averaging reveals that the immature MA lattice of L20K/E73K/A82T closely resembles the wild type. However, mature virions of the triple mutant lack a detectable MA lattice, in stark contrast to both the wild type and L20K mutant. All-atom molecular dynamics simulations suggest that this absence results from destabilized inter-trimer interactions in the mature L20K/E73K/A82T MA. Furthermore, introducing additional mutations designed to disrupt the mature MA lattice does not impair particle infectivity. These findings suggest that an ordered, membrane-associated mature MA lattice is not essential for HIV-1 infectivity, providing new insights into the structural plasticity of the matrix during maturation and its functional role in the viral lifecycle.

microbiology↗

bioRxiv2024

Structural insights into inhibitor mechanisms on immature HIV-1 Gag lattice revealed by high-resolution in situ single-particle cryo-EM

HIV-1 inhibitors, such as Bevirimat (BVM) and Lenacapavir (LEN), block the production and maturation of infectious virions. However, their mechanisms remain unclear due to the absence of high-resolution structures for BVM complexes and LENs structural data being limited to the mature capsid. Utilizing perforated virus-like particles (VLPs) produced from mammalian cells, we developed an approach to determine in situ cryo-electron microscopy (cryo-EM) structures of HIV-1 with inhibitors. This allowed for the first structural determination of the native immature HIV-1 particle with BVM and LEN bound inside the VLPs at high resolutions. Our findings offer a more accurate model of BVM engaging the Gag lattice and, importantly, demonstrate that LEN not only binds the mature capsid but also targets the immature lattice in a distinct manner. The binding of LEN induces a conformational change in the capsid protein (CA) region and alters the architecture of the Gag lattice, which may affect the maturation process. These insights expand our understanding of the inhibitory mechanisms of BVM and LEN on HIV-1 and provide valuable clues for the design of future inhibitors.

biochemistry↗

bioRxiv2024

The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents which potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into Phase 2a clinical trials. Previous cell culture based viral breakthrough assays identified the HIV-1(Y99H/A128T IN) variant that confers substantial resistance to this inhibitor. Here, we have elucidated the unexpected mechanism of viral resistance to PIR. While both Tyr99 and Ala128 are positioned within the inhibitor binding V-shaped cavity at the IN catalytic core domain (CCD) dimer interface, the Y99H/A128T IN mutations did not substantially affect direct binding of PIR to the CCD dimer or functional oligomerization of full-length IN. Instead, the drug-resistant mutations introduced a steric hindrance at the inhibitor mediated interface between CCD and C-terminal domain (CTD) and compromised CTD binding to the CCDY99H/A128T + PIR complex. Consequently, full-length INY99H/A128T was substantially less susceptible to the PIR induced hyper-multimerization than the WT protein, and HIV-1(Y99H/A128T IN) conferred >150- fold resistance to the inhibitor compared to the WT virus. By rationally modifying PIR we have developed its analog EKC110, which readily induced hyper-multimerization of INY99H/A128T in vitro and was [~]14-fold more potent against HIV-1(Y99H/A128T IN) than the parent inhibitor. These findings suggest a path for developing improved PIR chemotypes with a higher barrier to resistance for their potential clinical use. IMPORTANCEAntiretroviral therapies save the lives of millions of people living with HIV (PLWH). However, evolution of multi-drug-resistant viral phenotypes is a major clinical problem, and there are limited or no treatment options for heavily treatment-experienced PLWH. Allosteric HIV-1 integrase inhibitors (ALLINIs) are a novel class of antiretroviral compounds which work by a unique mechanism of binding to the non-catalytic site on the viral protein and inducing aberrant integrase multimerization. Accordingly, ALLINIs potently inhibit both wild type HIV-1 and all drug-resistant viral phenotypes that have so far emerged against currently used therapies. Pirmitegravir, a highly potent and safe investigational ALLINI, is currently advancing through clinical trials. Here we have elucidated structural and mechanistic bases behind the emergence of HIV-1 integrase mutations in infected cell that confer resistance to pirmitegravir. In turn, our findings allowed us to rationally develop an improved ALLINI with substantially enhanced potency against the pirmitegravir resistant virus.

microbiology↗

bioRxiv2023

Elasticity of the HIV-1 Core Facilitates Nuclear Entry and Infection

HIV-1 infection requires passage of the viral core through the nuclear pore of the cell, a process that depends on functions of the viral capsid 1,2. Recent studies have shown that HIV- 1 cores enter the nucleus prior to capsid disassembly 3-5. Interactions with the nuclear pore complex are necessary but not sufficient for nuclear entry, and the mechanism by which the viral core traverses the comparably sized nuclear pore is unknown. Here we show that the HIV-1 core is highly elastic and that this property is linked to nuclear entry and infectivity. Using atomic force microscopy-based approaches, we found that purified wild type cores rapidly returned to their normal conical morphology following a severe compression. Results from independently performed molecular dynamic simulations of the mature HIV-1 capsid also revealed its elastic property. Analysis of four HIV-1 capsid mutants that exhibit impaired nuclear entry revealed that the mutant viral cores are brittle. Suppressors of the mutants restored elasticity and rescued infectivity and nuclear entry. Elasticity was also reduced by treatment of cores with the capsid-targeting compound PF74 and the antiviral drug lenacapavir. Our results indicate that capsid elasticity is a fundamental property of the HIV-1 core that enables its passage through the nuclear pore complex, thereby facilitating infection. These results provide new insights into the mechanisms of HIV-1 nuclear entry and the antiviral mechanisms of HIV-1 capsid inhibitors.

biophysics↗

bioRxiv2023

Molecular architecture and conservation of an immature human endogenous retrovirus

A significant part of the human genome consists of endogenous retroviruses sequences. Human endogenous retrovirus K (HERV-K) is the most recently acquired endogenous retrovirus, is activated and expressed in many cancers and amyotrophic lateral sclerosis and possibly contributes to the aging process. To understand the molecular architecture of endogenous retroviruses, we determined the structure of immature HERV-K from native virus-like particles (VLPs) using cryo-electron tomography and subtomogram averaging (cryoET STA). The HERV-K VLPs show a greater distance between the viral membrane and immature capsid lattice, correlating with the presence of additional peptides, SP1 and p15, between the capsid (CA) and matrix (MA) proteins compared to the other retroviruses. The resulting cryoET STA map of the immature HERV-K capsid at 3.2 [A] resolution shows a hexamer unit oligomerized through a 6-helix bundle which is further stabilized by a small molecule in the same way as the IP6 in immature HIV-1 capsid. The HERV-K immature CA hexamer assembles into the immature lattice via highly conserved dimmer and trimer interfaces, whose interactions were further detailed through all-atom molecular dynamics simulations and supported by mutational studies. A large conformational change mediated by the flexible linker between the N-terminal and the C-terminal domains of CA occurs between the immature and the mature HERV-K capsid protein, analogous to HIV-1. Comparison between HERV-K and other retroviral immature capsid structures reveals a highly conserved mechanism for the assembly and maturation of retroviruses across genera and evolutionary time.

microbiology↗

bioRxiv2022

Performance efficient macromolecular mechanics via sub-nanometer shape based coarse graining

Dimensionality reduction via coarse grain modeling has positioned itself as an indispensable tool for decades, particularly for biomolecular simulations where atomic systems encompass hundreds of millions of atoms. While distinct flavors of coarse grain modeling exist, those occupying the coarse end of the spectrum are typically knowledge based, relying on a priori information to parameterize models, thus hindering general predictive capability. Here, we present an algorithmic and transferable approach known as shape based coarse graining (SBCG) which employs unsupervised machine learning via competitive Hebbian adaptation to construct coarse molecules that perfectly represent atomistic topologies. We show how SBCG provides ample control over model granularity, and we provide a quantitative metric for selection thereof. Parameter optimization, inclusion of small molecule species, as well as simulation configuration are discussed in detail. Our method and its implementation is made available as part of the CGBuilder plugin, present in the widely-used visual molecular dynamics (VMD) and nanoscale molecular dynamics (NAMD) software suites. We demonstrate applications of our method with a variety of systems from the inositol hexaphosphate-bound, full-scale HIV-1 capsid to heteromultimeric cofilin-2-bound actin filaments. Overall, we show that SBCG provides a simple yet robust approach to coarse graining that requires minimal user input and lacks any ad hoc interactions between protein domains. Furthermore, because the Hamiltonian employed in SBCG is CHARMM compatible, SBCG takes full advantage of the latest GPU-accelerated NAMD3 yielding molecular sampling of over a microsecond per day for systems that span micrometers.

biophysics↗

bioRxiv2022

Structural Basis of HIV-1 Maturation Inhibitor Binding and Activity

HIV-1 maturation inhibitors (MIs) interfere with the final step in the viral lifecycle by disrupting the ordered proteolytic processing of the viral Gag polyprotein into its individual domains. Bevirimat (BVM) and its analogs interfere with the final catalytic cleavage of spacer peptide 1 (SP1) from the capsid protein (CA) C-terminal domain (CACTD), by binding to and stabilizing the CACTD-SP1 region. MIs are under development as alternative drugs to augment current antiretroviral therapies. Although promising, their mechanism of action and associated virus resistance pathways remain poorly understood at the molecular, biochemical, and structural levels. Here, we report atomic-resolution magic angle spinning (MAS) NMR structures of microcrystalline assemblies of CACTD-SP1 complexed with BVM and/or the assembly cofactor inositol hexakisphosphate (IP6). BVM and IP6 can bind simultaneously to SP1, with BVM positioned in the center of its 6-helix bundle in a unique conformation. Importantly, the NMR-observed structural effects of BVM on IP6 binding suggest that the inhibitor stabilizes the 6-helix bundle in multiple ways. In addition, BVM-resistant SP1-A1V and SP1-V7A variants exhibit distinct conformational and binding characteristics. Taken together, our results reveal a novel allosteric mechanism by which BVM disrupts maturation and provide a structural explanation for BVM resistance as well as important guidance for the design of new MIs.

biophysics↗

bioRxiv2022

Equilibrium dynamics of the pre- and post-cleavage regions of SP1 are separately shifted by the HIV-1 maturation inhibitor Bevirimat

Human immunodeficiency virus type 1 (HIV-1) assembly and maturation proceeds in two distinct steps. During assembly, viral Gag oligomerizes into a hexagonal polyprotein lattice incorporating the capsid protein (CA) and spacer peptide 1 (SP1) domains, that constitute the immature Gag lattice. During maturation, CTD-SP1 hexamers formed in the previous step are cleaved by HIV-1 protease, causing a dramatic rearrangement of the immature virion to its mature, infectious form. The first-generation maturation inhibitor (MI) bevirimat (BVM) is reported to block the final cleavage between CA and SP1, thus blocking HIV maturation. In contrast, the host factor inositol hexakisphosphate (IP6) is a co-factor of Gag assembly and facilitates the formation of a quaternary arrangement of SP1 known as the six helix bundle (6HB). Here, starting from a MAS NMR structure and using atomistic free energy calculations, we establish that binding of BVM and IP6 to the immature lattice lacks any cooperativity or avidity. Furthermore, we rationalize the molecular origin of HIV resistance to BVM by determining the role of BVM on the stability of the 6HB and by revealing that SP1 shows independent dynamics for its pre- and post-cleavage regions. Finally, results from our simulations permit us to propose a novel chemical scaffold for the design of maturation inhibitors based on BVM and IP6.

biophysics↗

bioRxiv2021

HIV-1 Mutants that Escape the Cytotoxic T-Lymphocytes are Defective in Viral DNA Integration

ABSTRACT HIV-1 replication is durably controlled in certain untreated HIV-1-infected individuals expressing particular human leukocyte antigens (HLA). These HLAs tag infected cells for elimination by presenting specific viral epitopes to CD8+ cytotoxic T-lymphocytes (CTL). In individuals expressing HLA-B27, CTLs primarily target the capsid protein (CA)-derived KK10 epitope. Selection of CA mutation R264K helps HIV-1 escape the CTL response but severely diminishes virus infectivity. Here we report that the R264K mutation-associated infectivity defect arises primarily from impaired viral DNA integration. Strikingly, selection of the compensatory CA mutation S173A or depletion of host cyclophilin A largely rescues the R264K-associated integration and infectivity defects. Collectively, our study reveals novel mechanistic insights into the fitness defect incurred by an HIV-1 variant escaping a CA-directed CTL response.

microbiology↗

bioRxiv2021

Full scale structural, mechanical and dynamical properties of HIV-1 liposomes.

Enveloped viruses are enclosed by a lipid membrane inside of which are all of the components necessary for the virus life cycle; viral proteins, the viral genome and metabolites. Viral envelopes are lipid bilayers that adopt morphologies ranging from spheres to tubes. The envelope is derived from the host cell during viral replication. Thus, the composition of the bilayer depends on the complex constitution of lipids from the host-cells organelle(s) where assembly and/or budding of the viral particle occurs. Here, molecular dynamics (MD) simulations of authentic, asymmetric HIV-1 liposomes are used to derive a unique level of resolution of its full-scale structure, mechanics and dynamics. Analysis of the structural properties reveal the distribution of thicknesses of the bilayers over the entire liposome as well as its global fluctuations. Moreover, full-scale mechanical analyses are employed to derive the global bending rigidity of HIV-1 liposomes. Finally, dynamical properties of the lipid molecules reveal important relationships between their 3D diffusion, the location of lipid-rafts and the asymmetrical composition of the envelope. Overall, our simulations reveal complex relationships between the rich lipid composition of the HIV-1 liposome and its structural, mechanical and dynamical properties with critical consequences to different stages of HIV-1s life cycle.

biophysics↗

bioRxiv2020

Curvature of the retroviral capsid assembly is modulated by a molecular switch

During the maturation step, the capsid proteins (CAs) of a retrovirus assemble into polymorphic capsids, whose acute curvature is largely determined by insertion of 12 pentamers into the hexameric lattice. Despite years of intensive research, it remains elusive how the CA switches its conformation between the quasi-equivalent pentameric and hexameric assemblies to generate the acute curvature in the capsid. Here we report the high-resolution structural model of the RSV CA T=1 capsid. By comparing with our prior model of the RSV CA tubular assembly consisting entirely of hexameric lattices, we identify that a dozen of residues are the key to dictate the incorporation of acute curvatures in the capsid assembly. They undergo large torsion angle changes, which result a 34{degrees} rotation of the C-terminal domain relative to its N-terminal domain around the flexible interdomain linker, without substantial changes of either the conformation of individual domains or the assembly contact interfaces. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/424437v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@40cf38org.highwire.dtl.DTLVardef@e490beorg.highwire.dtl.DTLVardef@1dae0c5org.highwire.dtl.DTLVardef@dac850_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗