Host factor protein Cyclophilin A (CypA) regulates HIV-1 viral infectivity through direct interactions with the viral capsid, by an unknown mechanism. CypA can either promote or inhibit viral infection, depending on host cell type and HIV-1 capsid (CA) protein sequence. We have examined the role of conformational dynamics on the nanosecond to millisecond timescale in HIV-1 CA assemblies in the escape from CypA dependence, by magic-angle spinning (MAS) NMR and molecular dynamics (MD). Through the analysis of backbone 1H-15N and 1H-13C dipolar tensors and peak intensities from 3D MAS NMR spectra of wild-type and the A92E and G94D CypA escape mutants, we demonstrate that assembled CA is dynamic, particularly in loop regions. The CypA loop in assembled wild-type CA from two strains exhibits unprecedented mobility on the nanosecond to microsecond timescales, and the experimental NMR dipolar order parameters are in quantitative agreement with those calculated from MD trajectories. Remarkably, the CypA loop dynamics of wild-type CA HXB2 assembly is significantly attenuated upon CypA binding, and the dynamics profiles of the A92E and G94D CypA escape mutants closely resemble that of wild-type CA assembly in complex with CypA. These results suggest that CypA loop dynamics is a determining factor in HIV-1's escape from CypA dependence.
The host cell factor cyclophilin A (CypA) interacts directly with the HIV-1 capsid and regulates viral infectivity. Although the crystal structure of CypA in complex with the N-terminal domain of the HIV-1 capsid protein (CA) has been known for nearly two decades, how CypA interacts with the viral capsid and modulates HIV-1 infectivity remains unclear. We determined the cryoEM structure of CypA in complex with the assembled HIV-1 capsid at 8-Å resolution. The structure exhibits a distinct CypA-binding pattern in which CypA selectively bridges the two CA hexamers along the direction of highest curvature. EM-guided all-atom molecular dynamics simulations and solid-state NMR further reveal that the CypA-binding pattern is achieved by single-CypA molecules simultaneously interacting with two CA subunits, in different hexamers, through a previously uncharacterized non-canonical interface. These results provide new insights into how CypA stabilizes the HIV-1 capsid and is recruited to facilitate HIV-1 infection.
Membrane transport constitutes one of the most fundamental processes in all living cells with proteins as major players. Proteins as channels provide highly selective diffusive pathways gated by environmental factors, and as transporters furnish directed, energetically uphill transport consuming energy. X-ray crystallography of channels and transporters furnishes a rapidly growing number of atomic resolution structures, permitting molecular dynamics (MD) simulations to reveal the physical mechanisms underlying channel and transporter function. Ever increasing computational power today permits simulations stretching up to 1 μsec, i.e., to physiologically relevant time scales. Membrane protein simulations presently focus on ion channels, on aquaporins, on protein-conducting channels, as well as on various transporters. In this review we summarize recent developments in this rapidly evolving field.
Orientation-selective cells in the striate cortex of higher animals are organized as a hierarchical topographic map oftwo stimulus features: (i) position in visual space and (ii) orientation. We show that the observed structure of the topographic map can arise from a principle of continuous mapping. For the realization of this principle we use a mathematical model that can be interpreted as an adaptive process changing a set of synaptic weights, or synaptic connection strengths, between two layers of cells. The patterns of orientation preference and selectivity generated by the model are similar to the patterns seen in the visual cortex of macaque monkey and cat and correspond to a neural projection that maps a more than two-dimensional feature space onto a two-dimensional cortical surface under the constraint that shape and position of the receptive fields of the neurons vary smoothly over the cortical surface.The striate cortex of higher animals contains a topographic representation of visual space in which are embedded neighborhood-preserving maps of several variables describing features such as position in visual space, line orientation, movement direction, and ocularity (1)(2)(3)(4). The representation of the multidimensional feature space onto the two-dimensional cortical sheet is achieved in a hierarchical fashion (5). The topographic projection ofthe retina establishes a primary order, and for each small region of the visual field there are patches or stripes of cells with similar feature preference (1, 3). In this report we restrict our discussion to the features position and orientation.Distribution of orientation-selective cells within the visual cortex of the cat, macaque monkey, and the tree shrew has been characterized by several groups (1, 3, 5-7). Various mechanisms have been proposed to explain the input-driven formation and the plasticity of cortical maps, and simulations have shown that some of these mechanisms can account for various aspects of the observed organization (8)(9)(10)(11)(12)(13)(14). In this article we will investigate a neural-network model for the formation of orientation columns. The model is based on the self-organizing feature map algorithm (15, 16), which incorporates several of the proposed mechanisms (9). This investigation differs from the previously published work in several respects-the most important being that (i) the combined formation of the retinotopic projection and the orientation column system are studied, (ii) the interactions between both maps are presented, and (iii) the variations in the spatial distribution of feature-selective cells found in different species are considered.The Principle of Continuous Mapping. Are there general principles that can explain the formation of these highly ordered patterns? To investigate this question we consider a mathematical model (based on refs. 15 and 16) that determines cell properties along the cortical surface such that the "optimal stimuli" of the cell vary as smoothly as possible. This constraint can be int...
Highlights d A cell organelle, the photosynthetic chromatophore, is modeled in atomistic detail d Segregation of protein complexes tunes chromatophore structure and function d The electrostatic environment of the organelle supports low light-adaptation d Distinct modes of quinone diffusion underpin efficient electron transfer dynamics
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