| 1. |
- Almlöf, Martin, et al.
(författare)
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Energetics of codon-anticodon recognition on the small ribosomal subunit
- 2007
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 46:1, s. 200-209
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Tidskriftsartikel (refereegranskat)abstract
- Recent crystal structures of the small ribosomal subunit have made it possible to examine the detailed energetics of codon recognition on the ribosome by computational methods. The binding of cognate and near-cognate anticodon stem loops to the ribosome decoding center, with mRNA containing the Phe UUU and UUC codons, are analyzed here using explicit solvent molecular dynamics simulations together with the linear interaction energy (LIE) method. The calculated binding free energies are in excellent agreement with experimental binding constants and reproduce the relative effects of mismatches in the first and second codon position versus a mismatch at the wobble position. The simulations further predict that the Leu2 anticodon stem loop is about 10 times more stable than the Ser stem loop in complex with the Phe UUU codon. It is also found that the ribosome significantly enhances the intrinsic stability differences of codon-anticodon complexes in aqueous solution. Structural analysis of the simulations confirms the previously suggested importance of the universally conserved nucleotides A1492, A1493, and G530 in the decoding process.
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| 2. |
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| 3. |
- Ander, Malin, 1983-, et al.
(författare)
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A preliminary open trial of individualised cognitive behavioural therapy for young survivors of cancer during adolescence: initial findings and conceptualisation of distress
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective: A subgroup of adolescent and young adult (AYA) survivors of cancer in adolescence report high levels of psychological distress. Empirically-supported treatments tailored to the concerns experienced by this population are lacking. The aims of this study were to (1) conduct a preliminary evaluation of an individualised cognitive behavioural therapy (CBT) intervention for adolescent and young adult (AYA) survivors of cancer during adolescence and (2) identify and conceptualise cancer-related psychological concerns using cognitive-behavioural theory.Methods: A single-arm trial in which ten AYA (17-25 years) survivors of cancer during adolescence were offered up to 15 sessions of individualised CBT guided by behavioural case formulations was undertaken. Clinical outcomes were assessed at baseline, post-treatment, and three months follow-up. Before commencing treatment, two individual qualitative interviews were conducted with each participant. Analysis of cancer-related concerns was guided by qualitative framework analysis and theoretical thematic analysis, and cognitive-behavioural theory was used to inform identification of themes.Results: Ten of 201 potential participants invited to participate were included resulting in an overall participation rate of 5%. Nine participants completed treatment and eight completed the follow-up assessment. The majority of concerns reported were cancer-related and conceptualised as social avoidance, fear and avoidance of emotions and bodily symptoms, low mood and unbalance in activity, and worry and rumination.Conclusions: Given significant difficulties with recruitment, further research is needed to examine barriers and the impact of mental health literacy and stigma on help seeking in the AYA cancer survivor population. Internet-administered CBT self-help tailored towards the main presenting concerns of AYA cancer survivors may be a promising solution.
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| 4. |
- Andér, Martin, 1979-
(författare)
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Computational Analysis of Molecular Recognition Involving the Ribosome and a Voltage Gated K+ Channel
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Over the last few decades, computer simulation techniques have been established as an essential tool for understanding biochemical processes. This thesis deals mainly with the application of free energy calculations to ribosomal complexes and a cardiac ion channel. The linear interaction energy (LIE) method is used to explore the energetic properties of the essential process of codon–anticodon recognition on the ribosome. The calculations show the structural and energetic consequences and effects of first, second, and third position mismatches in the ribosomal decoding center. Recognition of stop codons by ribosomal termination complexes is fundamentally different from sense codon recognition. Free energy perturbation simulations are used to study the detailed energetics of stop codon recognition by the bacterial ribosomal release factors RF1 and RF2. The calculations explain the vastly different responses to third codon position A to G substitutions by RF1 and RF2. Also, previously unknown highly specific water interactions are identified. The GGQ loop of ribosomal RFs is essential for its hydrolytic activity and contains a universally methylated glutamine residue. The structural effect of this methylation is investigated. The results strongly suggest that the methylation has no effect on the intrinsic conformation of the GGQ loop, and, thus, that its sole purpose is to enhance interactions in the ribosomal termination complex. A first microscopic, atomic level, analysis of blocker binding to the pharmaceutically interesting potassium ion channel Kv1.5 is presented. A previously unknown uniform binding mode is identified, and experimental binding data is accurately reproduced. Furthermore, problems associated with pharmacophore models based on minimized gas phase ligand conformations are highlighted. Generalized Born and Poisson–Boltzmann continuum models are incorporated into the LIE method to enable implicit treatment of solvent, in an effort to improve speed and convergence. The methods are evaluated and validated using a set of plasmepsin II inhibitors.
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| 5. |
- Ander, Malin, et al.
(författare)
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Development of health-related quality of life and symptoms of anxiety and depression among persons diagnosed with cancer during adolescence : a 10-year follow-up study
- 2016
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Ingår i: Psycho-Oncology. - : Wiley. - 1057-9249 .- 1099-1611. ; 25:5, s. 582-589
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The main aim was to investigate the development of health-related quality of life (HRQOL) and symptoms of anxiety and depression in a cohort diagnosed with cancer during adolescence from shortly after up to 10 years after diagnosis.Methods: Participants (n = 61) completed the SF-36 and the HADS shortly; six, 12, and 18 months; and two, three, four, and 10 years (n = 28) after diagnosis. Polynomial change trajectories were used to model development.Results: Polynomial change trajectories showed an initial increase which abated over time into a decrease which abated over time for the SF-36 subscales Mental Health and Vitality; an initial decline which abated over time into an increase for HADS anxiety; and an initial decline which abated over time into an increase which abated over time for HADS depression. The SF-36 mental component summary showed no change from two to 10 years after diagnosis whereas the SF-36 physical component summary showed an increase from two years after diagnosis which declined over time. Ten years after diagnosis 29% reported possible anxiety.Conclusions: Development of HRQOL and symptoms of anxiety and depression appears to be nonlinear among persons diagnosed with cancer during adolescence. Well into permanent survivorship an increase in symptoms of anxiety is shown and approximately a third of the participants report possible anxiety. The findings indicate the need for: studies designed to pinpoint the times of highest psychological risk, clinical follow-up focusing on psychological problems, and development of effective psychological interventions for survivors of adolescent cancer
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| 6. |
- Andér, Martin, et al.
(författare)
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Does glutamine methylation affect the intrinsic conformation of the universally conserved GGQ motif in ribosomal release factors?
- 2009
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Ingår i: Biochemistry. - Washington, DC, USA : American Chemical Society. - 0006-2960 .- 1520-4995. ; 48:15, s. 3483-3489
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Tidskriftsartikel (refereegranskat)abstract
- The GGQ motif is the only universally conserved feature of ribosomal class 1 release factors. Mutational experiments and structural studies have suggested that the glutamine residue of the GGQ motif Q 185 in human eRF1 numbering) is critical for catalysis of the termination reaction on the ribosome. Furthermore, it has been established that Q185 is NE methylated in prokaryotes as well as eukaryotes, and that methylation significantly enhances the catalytic activity. It is, however, not known whether this methylation affects the intrinsic structure of the free release factor, which could be important for its interaction with the ribosome. In this work, we report molecular dynamics simulations, starting from 25 different NMR structures of human eRF1, in addressing this problem. The results show that there is no such structural effect on the free release factor caused by the NE methylation of Q185, suggesting that its role is intimately associated with the ribosome environment.
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| 8. |
- Andér, Martin, 1979-, et al.
(författare)
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Ligand binding to the voltage-gated Kv1.5 potassium channel in the open state - Docking and computer simulations of a homology model
- 2008
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Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 94:3, s. 820-831
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Tidskriftsartikel (refereegranskat)abstract
- The binding of blockers to the human voltage-gated Kv1.5 potassium ion channel is investigated using a three-step procedure consisting of homology modeling, automated docking, and binding free energy calculations from molecular dynamics simulations, in combination with the linear interaction energy method. A reliable homology model of Kv1.5 is constructed using the recently published crystal structure of the Kv1.2 channel as a template. This model is expected to be significantly more accurate than earlier ones based on less similar templates. Using the three-dimensional homology model, a series of blockers with known affinities are docked into the cavity of the ion channel and their free energies of binding are calculated. The predicted binding free energies are in very good agreement with experimental data and the binding is predicted to be mainly achieved through nonpolar interactions, whereas the relatively small differences in the polar contribution determine the specificity. Apart from confirming the importance of residues V505, I508, V512, and V516 for ligand binding in the cavity, the results also show that A509 and P513 contribute significantly to the nonpolar binding interactions. Furthermore, we find that pharmacophore models based only on optimized free ligand conformations may not necessarily capture the geometric features of ligands bound to the channel cavity. The calculations herein give a detailed structural and energetic picture of blocker binding to Kv1.5 and this model should thus be useful for further ligand design efforts.
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