| 1. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Crean, Rory M., et al.
(författare)
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Harnessing Conformational Plasticity to Generate Designer Enzymes
- 2020
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:26, s. 11324-11342
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Forskningsöversikt (refereegranskat)abstract
- Recent years have witnessed an explosion of interest in understanding the role of conformational dynamics both in the evolution of new enzymatic activities from existing enzymes and in facilitating the emergence of enzymatic activity de novo on scaffolds that were previously non-catalytic. There are also an increasing number of examples in the literature of targeted engineering of conformational dynamics being successfully used to alter enzyme selectivity and activity. Despite the obvious importance of conformational dynamics to both enzyme function and evolvability, many (although not all) computational design approaches still focus either on pure sequence-based approaches or on using structures with limited flexibility to guide the design. However, there exist a wide variety of computational approaches that can be (re)purposed to introduce conformational dynamics as a key consideration in the design process. Coupled with laboratory evolution and more conventional existing sequence- and structure-based approaches, these techniques provide powerful tools for greatly expanding the protein engineering toolkit. This Perspective provides an overview of evolutionary studies that have dissected the role of conformational dynamics in facilitating the emergence of novel enzymes, as well as advances in computational approaches that allow one to target conformational dynamics as part of enzyme design. Harnessing conformational dynamics in engineering studies is a powerful paradigm with which to engineer the next generation of designer biocatalysts.
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| 3. |
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| 4. |
- Gardner, Jasmine M., et al.
(författare)
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Energetics of Flap Opening in HIV-1 Protease : String Method Calculations
- 2019
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 123:45, s. 9584-9591
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Tidskriftsartikel (refereegranskat)abstract
- HIV-1 protease (PR) is the viral protein responsible for virion maturation, and its mechanisms of action remain incompletely understood. PR is dimeric and contains two flexible, symmetry-related flaps, which act as a gate to inhibit access to the binding pocket and hold the polypeptide substrate in the binding pocket once bound. Wide flap opening, a conformational change assumed to be necessary for substrate binding, is a rare event in the closed and bound form. In this study, we use molecular dynamics (MD) simulations and advanced MD techniques including temperature acceleration and string method in collective variables to study the conformational changes associated with substrate unbinding of both wild-type and F99Y mutant PR. The F99Y mutation is shown via MD to decouple the closing of previously unrecognized distal pockets from substrate unbinding. To determine whether or not the F99Y mutation affects the energetic cost of wide flap opening, we use string method in collective variables to determine the minimum free-energy mechanism for wide flap opening in concert with distal pocket closing. The results indicate that the major energetic cost in flap opening is disengagement of the two flap-tip Ile50 residues from each other and is not affected by the F99Y mutation.
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| 5. |
- van der Wijngaart, Wouter, et al.
(författare)
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Intervention strategies against COVID-19 and their estimated impact on Swedish healthcare capacity
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- ObjectivesDuring March 2020, the COVID-19 pandemic has rapidly spread globally, and non-pharmaceutical interventions are being used to reduce both the load on the healthcare system as well as overall mortality.DesignIndividual-based transmission modelling using Swedish demographic and Geographical Information System data and conservative COVID-19 epidemiological parameters.SettingSwedenParticipantsA model to simulate all 10.09 million Swedish residents.Interventions5 different non-pharmaceutical public-health interventions including the mitigation strategy of the Swedish government as of 10 April; isolation of the entire household of confirmed cases; closure of schools and non-essential businesses with or without strict social distancing; and strict social distancing with closure of schools and non-essential businesses.Main outcome measuresEstimated acute care and intensive care hospitalisations, COVID-19 attributable deaths, and infections among healthcare workers from 10 April until 29 June.FindingsOur model for Sweden shows that, under conservative epidemiological parameter estimates, the current Swedish public-health strategy will result in a peak intensive-care load in May that exceeds pre-pandemic capacity by over 40-fold, with a median mortality of 96,000 (95% CI 52,000 to 183,000). The most stringent public-health measures examined are predicted to reduce mortality by approximately three-fold. Intensive-care load at the peak could be reduced by over two-fold with a shorter period at peak pandemic capacity.ConclusionsOur results predict that, under conservative epidemiological parameter estimates, current measures in Sweden will result in at least 40-fold over-subscription of pre-pandemic Swedish intensive care capacity, with 15.8 percent of Swedish healthcare workers unable to work at the pandemic peak. Modifications to ICU admission criteria from international norms would further increase mortality.What is already known?-The COVID-19 pandemic has spread rapidly in Europe and globally since March 2020.-Mitigation and suppression methods have been suggested to slow down or halt the spread of the COVID-19 pandemic. Most European countries have enacted strict suppression measures including lockdown, school closures, enforced social distancing; while Sweden has chosen a different strategy of milder mitigation as of today (10 April 2020).-Different national policy decisions have been justified by socio-geographic differences among countries. Such differences as well as the tempo and stringency of public-health interventions are likely to affect the impact on each country’s mortality and healthcare system.What this study adds?-Individual-based modelling of COVID-19 spread using Swedish demographics and conservative epidemiological assumptions indicates that the peak of the number of hospitalised patients with COVID-19 can be expected in early May under the current strategy, shifted earlier and attenuated with more stringent public health measures.-Healthcare needs are expected to substantially exceed pre-pandemic capacity even if the most aggressive interventions considered were implemented in the coming weeks. In particular the need for intensive care unit beds will be at least 40-fold greater than the pre-pandemic capacity if the current strategy is maintained, and at least 10-fold greater if strategies approximating the most stringent in Europe are introduced by 10 April.-Our model predicts that, using median infection-fatality-rate estimates, at least 96,000 deaths would occur by 1 July without mitigation. Current policies reduce this number by approximately 15%, while even more aggressive social distancing measures, such as adding household isolation or mandated social distancing can reduce this number by more than 50%.
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