| 1. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 2. |
- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 3. |
- Kehoe, Laura, et al.
(författare)
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Make EU trade with Brazil sustainable
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 4. |
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| 5. |
- Koenekoop, Lucien, et al.
(författare)
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The Activation Parameters of a Cold-Adapted Short Chain Dehydrogenase Are Insensitive to Enzyme Oligomerization
- 2022
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 61:7, s. 514-522
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Tidskriftsartikel (refereegranskat)abstract
- The structural principles of enzyme cold adaptation are of fundamental interest both for understanding protein evolution and for biotechnological applications. It has become clear in recent years that structural flexibility plays a major role in tuning enzyme activity at low temperatures, which is reflected by characteristic changes in the thermodynamic activation parameters for psychrophilic enzymes, compared to those of mesophilic and thermophilic ones. Hence, increased flexibility of the enzyme surface has been shown to lead to a lower enthalpy and a more negative entropy of activation, which leads to higher activity in the cold. This immediately raises the question of how enzyme oligomerization affects the temperature dependence of catalysis. Here, we address this issue by computer simulations of the catalytic reaction of a cold-adapted bacterial short chain dehydrogenase in different oligomeric states. Reaction free energy profiles are calculated at different temperatures for the tetrameric, dimeric, and monomeric states of the enzyme, and activation parameters are obtained from the corresponding computational Arrhenius plots. The results show that the activation free energy, enthalpy, and entropy are remarkably insensitive to the oligomeric state, leading to the conclusion that assembly of the subunit interfaces does not compromise cold adaptation, even though the mobilities of interfacial residues are indeed affected.
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| 6. |
- Oanca, Gabriel, et al.
(författare)
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Efficient Empirical Valence Bond Simulations with GROMACS
- 2023
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 19:17, s. 6037-6045
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Tidskriftsartikel (refereegranskat)abstract
- We describe a protocol to perform empirical valence bond (EVB) simulations using GROMACS software. EVB is a fast and reliable method that allows one to determine the reaction free-energy profiles in complex systems, such as enzymes, by employing classical force fields to represent a chemical reaction. Therefore, running EVB simulations is basically as fast as any classical molecular dynamics simulation, and the method uses standard free-energy calculations to map the free-energy change along a given reaction path. To exemplify and validate our EVB implementation, we replicated two cases of our earlier enzyme simulations. One of these addresses the decomposition of the activation free energy into its enthalpic and entropic components, and the other is focused on calculating the overall catalytic effect of the enzyme compared to the same reaction in water. These two examples give virtually identical results to those obtained with programs that were specifically designed for EVB simulations and show that the GROMACS implementation is robust and can be used for very large systems.
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| 7. |
- van der Ent, Florian, et al.
(författare)
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Computational design of the temperature optimum of an enzyme reaction
- 2023
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 9:26
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Tidskriftsartikel (refereegranskat)abstract
- Cold-adapted enzymes are characterized both by a higher catalytic activity at low temperatures and by having their temperature optimum down-shifted, compared to mesophilic orthologs. In several cases, the optimum does not coincide with the onset of protein melting but reflects some other type of inactivation. In the psychrophilic a-amylase from an Antarctic bacterium, the inactivation is thought to originate from a specific enzyme-substrate interaction that breaks around room temperature. Here, we report a computational redesign of this enzyme aimed at shifting its temperature optimum upward. A set of mutations designed to stabilize the enzyme-substrate interaction were predicted by computer simulations of the catalytic reaction at different temperatures. The predictions were verified by kinetic experiments and crystal structures of the redesigned a-amylase, showing that the temperature optimum is indeed markedly shifted upward and that the critical surface loop controlling the temperature dependence approaches the target conformation observed in a mesophilic ortholog.
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| 8. |
- van der Ent, Florian
(författare)
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Computational Studies of the Temperature Dependence of Enzyme Catalysis
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Enzymes are known to adapt to low temperatures by lowering the enthalpy of activation of the key reaction steps. A lesser known property of some psychrophilic (cold-active) enzymes is an anomalous temperature optimum. For most enzymes the temperature optimum is determined by their denaturation temperature, but anomalous optima can occur well below the denaturation temperatures and there must thus be an alternative mechanism for their inactivation. A proposed mechanism examined in this thesis posits that there is a small conformational change or local unfolding which renders the enzyme inactive above its temperature optimum.In paper I this hypothesized mechanism of inactivation was used to guide the design of variants of a bacterial α-amylase from Pseudoalteromonas haloplanktis. This enzyme exhibits an anomalous optimum and it has been suggested that the breaking of a specific interaction is responsible for its inactivity at high temperatures. Using computational methods several designs were evaluated. When experimentally tested the best performing design raised the temperature optimum by about 6 °C. This finding demonstrates the validity of the assumed mechanism and the utility of computational modeling in enzyme design.In Paper II and III two closely related bacterial lipases were investigated, namely Lipase A from Bacillus subtilis and a psychrophilic homologue found in Bacillus pumulus. By combining computational methods and experiments, it was found that a single mutation site is responsible for the difference in activity and the mechanism of its effect on the catalysis was determined. The lipase found in Bacillus pumulus also exhibits an anomalous temperature optimum. Our preliminary findings regarding the mechanism of this optima are also presented.In the last publication, paper IV, computation of heat capacities of biomolecular systems from molecular dynamics simulations is investigated. A non-zero heat capacity of activation has been suggested to be responsible for curved Arrhenius plots in some enzymes. To further investigate these ideas, clear and robust methods for the evaluation of heat capacity must be employed. Our results show that a method relying on mean potential energies calculated at various temperatures converges quicker then alternative methods and is less sensitive to the choice of thermostat and other simulation parameters.
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| 9. |
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| 10. |
- van der Ent, Florian, et al.
(författare)
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Structure and Mechanism of a Cold-Adapted Bacterial Lipase
- 2022
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 61:10, s. 933-942
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Tidskriftsartikel (refereegranskat)abstract
- The structural origin of enzyme cold-adaptation has been the subject of considerable research efforts in recent years. Comparative studies of orthologous mesophilic-psychrophilic enzyme pairs found in nature are an obvious strategy for solving this problem, but they often suffer from relatively low sequence identity of the enzyme pairs. Small bacterial lipases adapted to distinctly different temperatures appear to provide an excellent model system for these types of studies, as they may show a very high degree of sequence conservation. Here, we report the first crystal structures of lipase A from the psychrophilic bacterium Bacillus pumilus, which confirm the high structural similarity to the mesophilic Bacillus subtilis enzyme, as indicated by their 81% sequence identity. We further employ extensive QM/MM calculations to delineate the catalytic reaction path and its energetics. The computational prediction of a rate-limiting deacylation step of the enzymatic ester hydrolysis reaction is verified by stopped-flow experiments, and steady-state kinetics confirms the psychrophilic nature of the B. pumilus enzyme. These results provide a useful benchmark for examining the structural basis of cold-adaptation and should now make it possible to disentangle the effects of the 34 mutations between the two enzymes on catalytic properties and thermal stability.
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