39 research outputs found
How proteins' negative cooperativity emerges from entropic optimisation of versatile collective fluctuations
The fact that allostery, a nonlocal signaling between distant binding sites, can arise mainly from the entropy balance of collective thermal modes, without conformational changes, is by now well known. However, the propensity to generate negative cooperativity is still unclear. Starting from an elastic-network picture of small protein complexes, in which effector binding is modeled by locally altering interaction strengths in lieu of adding a node-spring pair, we elucidate mechanisms particularly for such negative cooperativity. The approach via a few coupled harmonic oscillators with internal elastic strengths allows us to trace individual eigenmodes, their frequencies, and their statistical weights through successive bindings. We find that the alteration of the oscillators' couplings is paramount to covering both signs of allostery. Binding-modified couplings create a rich set of eigenmodes individually for each binding state, modes inaccessible to an ensemble of noninteracting units. The associated shifts of collective-mode frequencies, nonuniform with respect to modes and binding states, result in an enhanced optimizability, reflected by a subtle phase map of allosteric behaviors
Entropy and Barrier-Hopping Determine Conformational Viscoelasticity in Single Biomolecules
Biological macromolecules have complex and non-trivial energy landscapes,
endowing them a unique conformational adaptability and diversity in function.
Hence, understanding the processes of elasticity and dissipation at the
nanoscale is important to molecular biology and also emerging fields such as
nanotechnology. Here we analyse single molecule fluctuations in an atomic force
microscope (AFM) experiment using a generic model of biopolymer viscoelasticity
that importantly includes sources of local `internal' conformational
dissipation. Comparing two biopolymers, dextran and cellulose, polysaccharides
with and without the well-known `chair-to-boat' transition, reveals a signature
of this simple conformational change as minima in both the elasticity and
internal friction around a characteristic force. A calculation of two-state
populations dynamics offers a simple explanation in terms of an elasticity
driven by the entropy, and friction by barrier-controlled hopping, of
populations on a landscape. The microscopic model, allows quantitative mapping
of features of the energy landscape, revealing unexpectedly slow dynamics,
suggestive of an underlying roughness to the free energy.Comment: 25 pages, 7 figures, naturemag.bst, modified nature.cls
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Computational analysis of dynamic allostery and control in the SARS-CoV-2 main protease
The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has no publicly available vaccine or antiviral drugs at the time of writing. An attractive coronavirus drug target is the main protease (Mpro, also known as 3CLpro) because of its vital role in the viral cycle. A significant body of work has been focused on finding inhibitors which bind and block the active site of the main protease, but little has been done to address potential non-competitive inhibition, targeting regions other than the active site, partly because the fundamental biophysics of such allosteric control is still poorly understood. In this work, we construct an elastic network model (ENM) of the SARS-CoV-2 Mpro homodimer protein and analyse its dynamics and thermodynamics. We found a rich and heterogeneous dynamical structure, including allosterically correlated motions between the homodimeric protease's active sites. Exhaustive 1-point and 2-point mutation scans of the ENM and their effect on fluctuation free energies confirm previously experimentally identified bioactive residues, but also suggest several new candidate regions that are distant from the active site, yet control the protease function. Our results suggest new dynamically driven control regions as possible candidates for non-competitive inhibiting binding sites in the protease, which may assist the development of current fragment-based binding screens. The results also provide new insights into the active biophysical research field of protein fluctuation allostery and its underpinning dynamical structure
All the colours of the rainbow.
Our perception of colour has always been a source of fascination, so it's little wonder that studies of the phenomenon date back hundreds of years. What, though, can modern scientists learn from medieval literature — and how do we go about it
Coarse-grained model of entropic allostery
Many signaling functions in molecular biology require proteins to bind to substrates such as DNA in response to environmental signals such as the simultaneous binding to a small molecule. Examples are repressor proteins which may transmit information via a conformational change in response to the ligand binding. An alternative entropic mechanism of "allostery" suggests that the inducer ligand changes the intramolecular vibrational entropy, not just the mean static structure. We present a quantitative, coarse-grained model of entropic allostery, which suggests design rules for internal cohesive potentials in proteins employing this effect. It also addresses the issue of how the signal information to bind or unbind is transmitted through the protein. The model may be applicable to a wide range of repressors and also to signaling in trans-membrane proteins
Theoretical prediction and experimental measurement of isothermal extrudate swell of monodisperse and bidisperse polystyrenes
All the colours of the rainbow
Our perception of colour has always been a source of fascination, so it's little wonder that studies of the phenomenon date back hundreds of years. What, though, can modern scientists learn from medieval literature — and how do we go about it
Membraneless organelles formed by liquid-liquid phase separation increase bacterial fitness
Liquid-liquid phase separation is emerging as a crucial phenomenon in several
fundamental cell processes. A range of eukaryotic systems exhibit liquid
condensates. However, their function in bacteria, which in general lack
membrane-bound compartments, remains less clear. Here, we used high-resolution
optical microscopy to observe single bacterial aggresomes, nanostructured
intracellular assemblies of proteins, to undercover their role in cell stress.
We find that proteins inside aggresomes are mobile and undergo dynamic
turnover, consistent with a liquid state. Our observations are in quantitative
agreement with phase-separated liquid droplet formation driven by interacting
proteins under thermal equilibrium that nucleate following diffusive collisions
in the cytoplasm. We have discovered aggresomes in multiple species of
bacteria, and show that these emergent, metastable liquid-structured protein
assemblies increase bacterial fitness by enabling cells to tolerate
environmental stresses