Publications by authors named "Alexander J Pak"

Nanobody (Nb)-induced disassembly of surface array protein (Sap) S-layers, a two-dimensional paracrystalline protein lattice from , has been presented as a therapeutic intervention for lethal anthrax infections. However, only a subset of existing Nbs with affinity to Sap exhibit depolymerization activity, suggesting that affinity and epitope recognition are not enough to explain inhibitory activity. In this study, we performed all-atom molecular dynamics simulations of each Nb bound to the Sap binding site and trained a collection of machine learning classifiers to predict whether each Nb induces depolymerization.

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is a spore-forming gram-positive bacterium responsible for anthrax, an infectious disease with a high mortality rate and a target of concern due to bioterrorism and long-term site contamination. The entire surface of vegetative cells in exponential or stationary growth phase is covered in proteinaceous arrays called S-layers, composed of Sap or EA1 protein, respectively. The Sap S-layer represents an important virulence factor and cell envelope support structure whose paracrystalline nature is essential for its function.

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Molecular simulations of biomacromolecules that assemble into multimeric complexes remain a challenge due to computationally inaccessible length and time scales. Low-resolution and implicit-solvent coarse-grained modeling approaches using traditional nonbonded interactions (both pairwise and spherically isotropic) have been able to partially address this gap. However, these models may fail to capture the complex anisotropic interactions present at macromolecular interfaces unless higher-order interaction potentials are incorporated at the expense of the computational cost.

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Protein hydrogels represent an important and growing biomaterial for a multitude of applications, including diagnostics and drug delivery. We have previously explored the ability to engineer the thermoresponsive supramolecular assembly of coiled-coil proteins into hydrogels with varying gelation properties, where we have defined important parameters in the coiled-coil hydrogel design. Using Rosetta energy scores and Poisson-Boltzmann electrostatic energies, we iterate a computational design strategy to predict the gelation of coiled-coil proteins while simultaneously exploring five new coiled-coil protein hydrogel sequences.

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The outer membrane in Gram-negative bacteria consists of an asymmetric phospholipid-lipopolysaccharide bilayer that is densely packed with outer-membrane β-barrel proteins (OMPs) and lipoproteins. The architecture and composition of this bilayer is closely monitored and is essential to cell integrity and survival. Here we find that SlyB, a lipoprotein in the PhoPQ stress regulon, forms stable stress-induced complexes with the outer-membrane proteome.

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The "bottom-up" approach to coarse-graining, for building accurate and efficient computational models to simulate large-scale and complex phenomena and processes, is an important approach in computational chemistry, biophysics, and materials science. As one example, the Multiscale Coarse-Graining (MS-CG) approach to developing CG models can be rigorously derived using statistical mechanics applied to fine-grained, i.e.

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The maturation of HIV-1 capsid protein (CA) into a cone-shaped lattice capsid is critical for viral infectivity. CA can self-assemble into a range of capsid morphologies made of ~175 to 250 hexamers and 12 pentamers. The cellular polyanion inositol hexakisphosphate (IP6) has recently been demonstrated to facilitate conical capsid formation by coordinating a ring of arginine residues within the central cavity of capsid hexamers and pentamers.

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Large-scale computational molecular models provide scientists a means to investigate the effect of microscopic details on emergent mesoscopic behavior. Elucidating the relationship between variations on the molecular scale and macroscopic observable properties facilitates an understanding of the molecular interactions driving the properties of real world materials and complex systems (e.g.

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During the late stages of the HIV-1 lifecycle, immature virions are produced by the concerted activity of Gag polyproteins, primarily mediated by the capsid (CA) and spacer peptide 1 (SP1) domains, which assemble into a spherical lattice, package viral genomic RNA, and deform the plasma membrane. Recently, inositol hexakisphosphate (IP6) has been identified as an essential assembly cofactor that efficiently produces both immature virions and immature virus-like particles . To date, however, several distinct mechanistic roles for IP6 have been proposed on the basis of independent functional, structural, and kinetic studies.

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Lipid droplets (LDs) are organelles formed in the endoplasmic reticulum (ER) to store triacylglycerol (TG) and sterol esters. The ER protein seipin is key for LD biogenesis. Seipin forms a cage-like structure, with each seipin monomer containing a conserved hydrophobic helix and two transmembrane (TM) segments.

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The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes dissociation of the S1 domains and exposure of the fusion machinery, although the molecular details of this process have yet to be observed.

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Article Synopsis
  • - The assembly and maturation of HIV-1 depend on the cleavage of the Gag polyprotein, particularly at a key junction involving the capsid protein and a six-helix bundle (6HB).
  • - Bevirimat (BVM) is a maturation inhibitor that targets this 6HB to block proteolytic cleavage, but its exact mechanism and how mutant viruses evade it are not well understood.
  • - Through molecular dynamics simulations, the study found that BVM's effectiveness is linked to the preservation of the 6HB's symmetry, and two main escape mechanisms in mutant viruses lead to a loss of this symmetry, which helps the virus resist the inhibitor.
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The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind, fuse, and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes the preparation of the fusion machinery by dissociation of the S1 domains.

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Water is undoubtedly one of the most important molecules for a variety of chemical and physical systems, and constructing precise yet effective coarse-grained (CG) water models has been a high priority for computer simulations. To recapitulate important local correlations in the CG water model, explicit higher-order interactions are often included. However, the advantages of coarse-graining may then be offset by the larger computational cost in the model parameterization and simulation execution.

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A number of studies have constructed coarse-grained (CG) models of water to understand its anomalous properties. Most of these properties emerge at low temperatures, and an accurate CG model needs to be applicable to these low-temperature ranges. However, direct use of CG models parameterized from other temperatures, e.

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The CA (capsid) domain of immature HIV-1 Gag and the adjacent spacer peptide 1 (SP1) play a key role in viral assembly by forming a lattice of CA hexamers, which adapts to viral envelope curvature by incorporating small lattice defects and a large gap at the site of budding. This lattice is stabilized by intrahexameric and interhexameric CA-CA interactions, which are important in regulating viral assembly and maturation. We applied subtomogram averaging and classification to determine the oligomerization state of CA at lattice edges and found that CA forms partial hexamers.

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. Computer simulations of complete viral particles can provide theoretical insights into large-scale viral processes including assembly, budding, egress, entry, and fusion. Detailed atomistic simulations are constrained to shorter timescales and require billion-atom simulations for these processes.

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Collective action by inverse-Bin/Amphiphysin/Rvs (I-BAR) domains drive micron-scale membrane remodeling. The macroscopic curvature sensing and generation behavior of I-BAR domains is well characterized, and computational models have suggested various mechanisms on simplified membrane systems, but there remain missing connections between the complex environment of the cell and the models proposed thus far. Here, we show a connection between the role of protein curvature and lipid clustering in the relaxation of large membrane deformations.

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Unlabelled: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. Computer simulations of complete viral particles can provide theoretical insights into large-scale viral processes including assembly, budding, egress, entry, and fusion. Detailed atomistic simulations, however, are constrained to shorter timescales and require billion-atom simulations for these processes.

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Article Synopsis
  • The ESCRT complexes are crucial for processes like HIV-1 release, autophagosome closure, and cell division, with ESCRT-I being the primary complex that connects to HIV-1 Gag during virus release.
  • Researchers determined the crystal structure of the human ESCRT-I headpiece, revealing it consists of a helical assembly with a repeating pattern of 12 molecules, which was confirmed through electron microscopy.
  • Mutations in specific regions of the VPS28 protein prevent the formation of the ESCRT-I filaments, which impairs key cellular processes like HIV-1 release and autophagosome closure, highlighting the complex's important structural and functional roles.
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The tripartite-motif protein, TRIM5α, is an innate immune sensor that potently restricts retrovirus infection by binding to human immunodeficiency virus capsids. Higher-ordered oligomerization of this protein forms hexagonally patterned structures that wrap around the viral capsid, despite an anomalously low affinity for the capsid protein (CA). Several studies suggest TRIM5α oligomerizes into a lattice with a symmetry and spacing that matches the underlying capsid, to compensate for the weak affinity, yet little is known about how these lattices form.

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Protein-mediated membrane remodeling is a ubiquitous and critical process for proper cellular function. Inverse Bin/Amphiphysin/Rvs (I-BAR) domains drive local membrane deformation as a precursor to large-scale membrane remodeling. We employ a multiscale approach to provide the molecular mechanism of unusual I-BAR domain-driven membrane remodeling at a low protein surface concentration with near-atomistic detail.

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Coarse-grained (CG) models facilitate efficient simulation of complex systems by integrating out the atomic, or fine-grained (FG), degrees of freedom. Systematically derived CG models from FG simulations often attempt to approximate the CG potential of mean force (PMF), an inherently multidimensional and many-body quantity, using additive pairwise contributions. However, they currently lack fundamental principles that enable their extensible use across different thermodynamic state points, i.

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The early and late stages of human immunodeficiency virus (HIV) replication are orchestrated by the capsid (CA) protein, which self-assembles into a conical protein shell during viral maturation. Small molecule drugs known as capsid inhibitors (CIs) impede the highly regulated activity of CA. Intriguingly, a few CIs, such as PF-3450074 (PF74) and GS-CA1, exhibit effects at multiple stages of the viral lifecycle at effective concentrations in the pM to nM regimes, while the majority of CIs target a single stage of the viral lifecycle and are effective at nM to μM concentrations.

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Synopsis of recent research by authors named "Alexander J Pak"

  • - Alexander J Pak's recent research centers on the computational modeling and simulation of biomacromolecules, particularly in the context of protein interactions, assembly, and gelation dynamics, with implications for materials science and biophysics.
  • - His studies have advanced the understanding of coarse-grained representations of protein interfaces and explored the role of inositol hexakisphosphate in facilitating the assembly of viral capsids, highlighting significant mechanistic insights in HIV-1 assembly.
  • - Pak has also contributed to the design of protein hydrogels and the development of software tools for multiscale coarse-graining, indicating a strong emphasis on bridging theoretical simulations with practical applications in biomaterials and drug delivery systems.

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