| 1. |
- Caldararu, Octav, et al.
(författare)
-
Binding free energies in the SAMPL6 octa-acid host–guest challenge calculated with MM and QM methods
- 2018
-
Ingår i: Journal of Computer-Aided Molecular Design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 32:10, s. 1027-1046
-
Tidskriftsartikel (refereegranskat)abstract
- We have estimated free energies for the binding of eight carboxylate ligands to two variants of the octa-acid deep-cavity host in the SAMPL6 blind-test challenge (with or without endo methyl groups on the four upper-rim benzoate groups, OAM and OAH, respectively). We employed free-energy perturbation (FEP) for relative binding energies at the molecular mechanics (MM) and the combined quantum mechanical (QM) and MM (QM/MM) levels, the latter obtained with the reference-potential approach with QM/MM sampling for the MM → QM/MM FEP. The semiempirical QM method PM6-DH+ was employed for the ligand in the latter calculations. Moreover, binding free energies were also estimated from QM/MM optimised structures, combined with COSMO-RS estimates of the solvation energy and thermostatistical corrections from MM frequencies. They were performed at the PM6-DH+ level of theory with the full host and guest molecule in the QM system (and also four water molecules in the geometry optimisations) for 10–20 snapshots from molecular dynamics simulations of the complex. Finally, the structure with the lowest free energy was recalculated using the dispersion-corrected density-functional theory method TPSS-D3, for both the structure and the energy. The two FEP approaches gave similar results (PM6-DH+/MM slightly better for OAM), which were among the five submissions with the best performance in the challenge and gave the best results without any fit to data from the SAMPL5 challenge, with mean absolute deviations (MAD) of 2.4–5.2 kJ/mol and a correlation coefficient (R2) of 0.77–0.93. This is the first time QM/MM approaches give binding free energies that are competitive to those obtained with MM for the octa-acid host. The QM/MM-optimised structures gave somewhat worse performance (MAD = 3–8 kJ/mol and R2 = 0.1–0.9), but the results were improved compared to previous studies of this system with similar methods.
|
|
| 2. |
- Caldararu, Octav, et al.
(författare)
-
Water structure in solution and crystal molecular dynamics simulations compared to protein crystal structures
- 2020
-
Ingår i: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 10, s. 8435-8443
-
Tidskriftsartikel (refereegranskat)abstract
- The function of proteins is influenced not only by the atomic structure but also by the detailed structure of the solvent surrounding it. Computational studies of protein structure also critically depend on the water structure around the protein. Herein we compare the water structure obtained from molecular dynamics (MD) simulations of galectin-3 in complex with two ligands to crystallographic water molecules observed in the corresponding crystal structures. We computed MD trajectories both in a water box, which mimics a protein in solution, and in a crystallographic unit cell, which mimics a protein in a crystal. The calculations were compared to crystal structures obtained at both cryogenic and room temperature. Two types of analyses of the MD simulations were performed. First, the positions of the crystallographic water molecules were compared to peaks in the MD density after alignment of the protein in each snapshot. The results of this analysis indicate that all simulations reproduce the crystallographic water structure rather poorly. However, if we define the crystallographic water sites based on their distances to nearby protein atoms and follow these sites throughout the simulations, the MD simulations reproduce the crystallographic water sites much better. This shows that the failure of MD simulations to reproduce the water structure around proteins in crystal structures observed both in this and previous studies is caused by the problem of identifying water sites for a flexible and dynamic protein (traditionally done by overlaying the structures). Our local clustering approach solves the problem and shows that the MD simulations reasonably reproduce the water structure observed in crystals. Furthermore, analysis of the crystal MD simulations indicates a few water molecules that are close to unmodeled electron density peaks in the crystal structures, suggesting that crystal MD could be used as a complementary tool for identifying and modelling water in protein crystallography.
|
|
| 3. |
- Cronström, Anna, et al.
(författare)
-
Interpretation threshold values for patient-reported outcomes in patients participating in a digitally delivered first-line treatment program for hip or knee osteoarthritis
- 2023
-
Ingår i: Osteoarthritis and Cartilage Open. - : Elsevier. - 2665-9131. ; 5:3
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Establish proportions of patients reporting important improvement, acceptable symptoms and treatment failure and define interpretation threshold values for pain, patient-reported function and quality-of-life after participating in digital first-line treatment including education and exercise for hip and knee osteoarthritis (OA).Methods: Observational study. Responses to the pain Numeric Rating Scale (NRS, 0-10 best to worst), Knee injury and Osteoarthritis Outcome Score 12 (KOOS-12) and Hip disability and Osteoarthritis Outcome Score 12 (HOOS-12, both 0-100 worst to best) were obtained for 4383 (2987) and 20341 (1264) participants with knee (hip) OA at 3 and 12 months post intervention.. Threshold values for Minimal Important Change (MIC), Patient Acceptable Symptom State (PASS) and Treatment Failure (TF) were estimated using anchor-based predictive modeling.Results: 70–85% reported an important improvement in pain, function and quality of life after 3 and 12 months follow-up. 42% (3 months) and 51% (12 months) considered their current state as satisfactory, whereas 2-4% considered treatment failed. MIC values were -1 (NRS) and 0-4 (KOOS/HOOS-12) across follow-ups and joint affected. PASS threshold value for NRS was 3, and 53–73 for the KOOS/HOOS-12 subscales Corresponding values for TF were 5 (NRS) and 34–55 (KOOS/HOOS-12). Patients with more severe pain at baseline had higher MIC scores and accepted poorer outcomes at follow-ups.Conclusion: Threshold estimates aid in the interpretation of outcomes after first-line OA interventions assessed with NRS Pain and KOOS/HOOS-12. Baseline pain severity is important to consider when interpreting threshold values after first-line interventions in these patients.
|
|
| 4. |
- Dell'Isola, Andrea, et al.
(författare)
-
Within-person change in patient-reported outcomes and their association with the wish to undergo joint surgery during a digital first-line intervention for osteoarthritis
- 2023
-
Ingår i: Osteoarthritis and Cartilage. - 1063-4584 .- 1522-9653.
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: To study the association between within-person changes in patient-reported outcomes (PROMs) and wish for joint surgery during participation in a digital first-line intervention comprising exercise and education for knee/hip osteoarthritis (OA).Methods: Retrospective observational registry study. Participants enrolled between 01/06/2018 and 30/10/2021 with follow-up data at 3 months (n=13,961). We used asymmetric fixed effect (conditional) logistic regressions to study the association between change in wish to undergo surgery at last available time point (3,6,9 or 12 months) and improvement or worsening of PROMs pain (0-10), quality of life (EQ5D-5L, 0.243-0.976), overall health (0-10), activity impairment (0-10), walking difficulties (yes/no), fear of movement (yes/no) and Knee/Hip injury and Osteoarthritis Outcome Score 12 Items (KOOS-12/HOOS-12, 0-100) function and quality of life (QoL) subscales.Results: The proportion of participants wishing to undergo surgery declined by 2% (95% CI 1.9, 3.0), from 15.7% at the baseline to 13.3% at 3 months. Generally, improvements in PROMs were associated with reduced likelihood of wishing for surgery while worsening was associated with increased likelihood. For pain, activity impairment EQ-5D and KOOS/HOOS QoL, a worsening led to a change in the probability of wish for surgery of larger absolute magnitude than an improvement in the same PROM.Conclusions: Within-person improvements in PROMs are associated with reduced wish for surgery, while worsenings with an increased wish for surgery. Larger improvements in PROMs may be needed to match the magnitude of the change in wish for surgery associated with a worsening in the same PROM.
|
|
| 5. |
- Ekberg, Vilhelm, et al.
(författare)
-
Comparison of Grand Canonical and Conventional Molecular Dynamics Simulation Methods for Protein-Bound Water Networks
- 2022
-
Ingår i: ACS Physical Chemistry Au. - : American Chemical Society (ACS). - 2694-2445. ; 2:3, s. 247-259
-
Tidskriftsartikel (refereegranskat)abstract
- Water molecules play important roles in all biochemical processes. Therefore, it is of key importance to obtain information of the structure, dynamics, and thermodynamics of water molecules around proteins. Numerous computational methods have been suggested with this aim. In this study, we compare the performance of conventional and grand-canonical Monte Carlo (GCMC) molecular dynamics (MD) simulations to sample the water structure, as well GCMC and grid-based inhomogeneous solvation theory (GIST) to describe the energetics of the water network. They are evaluated on two proteins: the buried ligand-binding site of a ferritin dimer and the solvent-exposed binding site of galectin-3. We show that GCMC/MD simulations significantly speed up the sampling and equilibration of water molecules in the buried binding site, thereby making the results more similar for simulations started from different states. Both GCMC/MD and conventional MD reproduce crystal-water molecules reasonably for the buried binding site. GIST analyses are normally based on restrained MD simulations. This improves the precision of the calculated energies, but the restraints also significantly affect both absolute and relative energies. Solvation free energies for individual water molecules calculated with and without restraints show a good correlation, but with large quantitative differences. Finally, we note that the solvation free energies calculated with GIST are ∼5 times larger than those estimated by GCMC owing to differences in the reference state.
|
|
| 6. |
- Hörder, Helena, et al.
(författare)
-
Digitally Delivered Exercise and Education Treatment Program for Low Back Pain: Longitudinal Observational Cohort Study
- 2022
-
Ingår i: JMIR Rehabilitation and Assistive Technologies. - : JMIR Publications Inc.. - 2369-2529. ; 9:2, s. e38084-e38084
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Exercise and education is recommended as first-line treatment by evidence-based, international guidelines for low back pain (LBP). Despite consensus regarding the treatment, there is a gap between guidelines and what is offered to patients. Digital LBP treatments are an emerging way of delivering first-line treatment.Objective: The aim of this study is to evaluate outcomes after participation in a 3-month digitally delivered treatment program for individuals with subacute or chronic LBP.Methods: We analyzed data from 2593 consecutively recruited participants in a digitally delivered treatment program, available via the national health care system in Sweden. The program consists of video-instructed and progressive adaptable exercises, education through text lessons, and a chat and video function connecting participants with a personal physiotherapist. The primary outcome was mean change and proportion reaching a minimal clinically important change (MCIC) for LBP (2 points or 30% decrease) assessed with the numerical rating scale (average pain during the past week, discrete boxes, 0-10, best to worst). Secondary outcomes were mean change and proportion reaching MCIC (10 points or 30%) in disability, assessed with the Oswestry Disability Index (ODI; 0-100, best to worst) and a question on patient acceptable symptom state (PASS).Results: The mean participant age was 63 years, 73.85% (1915/2593) were female, 54.72% (1419/2593) had higher education, 50.56% (1311/2593) were retired, and the mean BMI was 26.5 kg/m2. Participants completed on average 84% of the prescribed exercises and lessons, with an adherence of ≥80% in 69.26% (1796/2593) and ≥90% in 50.13% (1300/2593) of the participants. Mean reduction in pain from baseline to 3 months was 1.7 (95% CI –1.8 to –1.6), corresponding to a 35% relative change. MCIC was reached by 58.50% (1517/2593) of participants. ODI decreased 4 points (95% CI –4.5 to –3.7), and 36.48% (946/2593) reached an MCIC. A change from no to yes in PASS was seen in 30.35% (787/2593) of participants. Multivariable analysis showed positive associations between reaching an MCIC in pain and high baseline pain (odds ratio [OR] 1.9, 95% CI 1.6-2.1), adherence (OR 1.5, 95% CI 1.3-1.8), and motivation (OR 1.2, 95% CI 1.0-1.5), while we found negative associations for wish for surgery (OR 0.6, 95% CI 0.5-0.9) and pain in other joints (OR 0.9, 95% CI 0.7-0.9). We found no associations between sociodemographic characteristics and pain reduction.Conclusions: Participants in this digitally delivered treatment for LBP had reduced pain at 3-month follow-up, and 58.50% (1517/2593) reported an MCIC in pain. Our findings suggest that digital treatment programs can reduce pain at clinically important levels for people with high adherence to treatment but that those with such severe LBP problems that they wish to undergo surgery may benefit from additional support.
|
|
| 7. |
- Kiadaliri, Ali, et al.
(författare)
-
Digital self-management of hip and knee osteoarthritis and trajectories of work and activity impairments
- 2023
-
Ingår i: BMC Musculoskeletal Disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 24, s. 1-11
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the trajectories of work and activity impairments among people participating in a digital self-management program for osteoarthritis (OA).METHODS: We conducted an observational longitudinal study using data for baseline, 3, 6, 9 and 12 months follow ups from people participating in a digital OA treatment between June 2018 and September 2021. The Work Productivity and Activity Impairment-Osteoarthritis (WPAI-OA) questionnaire was used to measure work and activity impairments. We applied linear mixed models and group-based trajectory modelling (GBTM) to assess the trajectories of work and activity impairments and their variability. Dominance analysis was performed to explore the relative importance of baseline characteristics in predicting the trajectory subgroup membership.RESULTS: A total of 14,676 participants with mean (± standard deviation) age 64.0 (± 9.1) years and 75.5% females were included. The adjusted mean improvements in work impairment from baseline were 5.8% (95% CI 5.3, 6.4) to 6.1% (95% CI 5.5, 6.8). The corresponding figures for activity impairment were 9.4% (95% CI 9.0, 9.7) to 11.3% (95% CI 10.8, 11.8). GBTM identified five (low baseline-declining, moderate baseline-declining, high baseline-declining, very high baseline-substantially declining, and very high baseline-persistent) and three (low baseline-declining, mild baseline-declining, high baseline-declining) subgroups with distinct trajectories of activity and work impairments. Dominance analysis showed that baseline pain was the most important predictor of membership in trajectory subgroups.CONCLUSION: While participation in a digital self-management program for OA was, on average, associated with improvements in work and activity impairments, there were substantial variations among the participants. Baseline pain may provide useful insights to predict trajectories of work and activity impairments.
|
|
| 8. |
- Kumar, Rohit, et al.
(författare)
-
Structure and Energetics of Ligand–Fluorine Interactions with Galectin-3 Backbone and Side-Chain Amides : Insight into Solvation Effects and Multipolar Interactions
- 2019
-
Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 14:16, s. 1528-1536
-
Tidskriftsartikel (refereegranskat)abstract
- Multipolar fluorine–amide interactions with backbone and side-chain amides have been described as important for protein–ligand interactions and have been used to improve the potency of synthetic inhibitors. In this study, fluorine interactions within a well-defined binding pocket on galectin-3 were investigated systematically using phenyltriazolyl-thiogalactosides fluorinated singly or multiply at various positions on the phenyl ring. X-ray structures of the C-terminal domain of galectin-3 in complex with eight of these ligands revealed potential orthogonal fluorine–amide interactions with backbone amides and one with a side-chain amide. The two interactions involving main-chain amides seem to have a strong influence on affinity as determined by fluorescence anisotropy. In contrast, the interaction with the side-chain amide did not influence affinity. Quantum mechanics calculations were used to analyze the relative contributions of these interactions to the binding energies. No clear correlation could be found between the relative energies of the fluorine–main-chain amide interactions and the overall binding energy. Instead, dispersion and desolvation effects play a larger role. The results confirm that the contribution of fluorine–amide interactions to protein–ligand interactions cannot simply be predicted, on geometrical considerations alone, but require careful consideration of the energetic components.
|
|
| 9. |
- Kumar, Rohit, et al.
(författare)
-
Substituted polyfluoroaryl interactions with an arginine side chain in galectin-3 are governed by steric-, desolvation and electronic conjugation effects
- 2019
-
Ingår i: Organic and Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 17:5, s. 1081-1089
-
Tidskriftsartikel (refereegranskat)abstract
- In the β-d-galactopyranoside-binding protein galectin-3, synthetic inhibitors substituted at the 3-position of a thiodigalactoside core cause the formation of an aglycone binding pocket through the displacement of an arginine residue (Arg144) from its position in the apoprotein. To examine in detail the role of different molecular interactions in this pocket, we have synthesized a series of nine 3-(4-(2,3,5,6-tetrafluorophenyl)-1,2,3-triazol-1-yl)-thiogalactosides with different para substituents and measured their affinities to galectin-3 using a fluorescence polarization assay. High-resolution crystal structures (<1.3 Å) have been determined for five of the ligands in complex with the C-terminal domain of galectin-3. The binding affinities are rationalised with the help of the three-dimensional structures and quantum-mechanical calculations. Three effects seem to be involved: Firstly, the binding pocket is too small for the largest ligands with ethyl and methyl. Secondly, for the other ligands, the affinity seems to be determined mainly by desolvation effects, disfavouring the polar substituents, but this is partly counteracted by the cation-π interaction with Arg144, which stacks on top of the substituted tetrafluorophenyl group in all complexes. The results provide detailed insight into interactions of fluorinated phenyl moieties with arginine-containing protein binding sites and the complex interplay of different energetic components in defining the binding affinity.
|
|
| 10. |
- Misini Ignjatović, Majda, et al.
(författare)
-
Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations
- 2016
-
Ingår i: Journal of Computer-Aided Molecular Design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 30:9, s. 707-730
-
Tidskriftsartikel (refereegranskat)abstract
- We have estimated the binding affinity of three sets of ligands of the heat-shock protein 90 in the D3R grand challenge blind test competition. We have employed four different methods, based on five different crystal structures: first, we docked the ligands to the proteins with induced-fit docking with the Glide software and calculated binding affinities with three energy functions. Second, the docked structures were minimised in a continuum solvent and binding affinities were calculated with the MM/GBSA method (molecular mechanics combined with generalised Born and solvent-accessible surface area solvation). Third, the docked structures were re-optimised by combined quantum mechanics and molecular mechanics (QM/MM) calculations. Then, interaction energies were calculated with quantum mechanical calculations employing 970–1160 atoms in a continuum solvent, combined with energy corrections for dispersion, zero-point energy and entropy, ligand distortion, ligand solvation, and an increase of the basis set to quadruple-zeta quality. Fourth, relative binding affinities were estimated by free-energy simulations, using the multi-state Bennett acceptance-ratio approach. Unfortunately, the results were varying and rather poor, with only one calculation giving a correlation to the experimental affinities larger than 0.7, and with no consistent difference in the quality of the predictions from the various methods. For one set of ligands, the results could be strongly improved (after experimental data were revealed) if it was recognised that one of the ligands displaced one or two water molecules. For the other two sets, the problem is probably that the ligands bind in different modes than in the crystal structures employed or that the conformation of the ligand-binding site or the whole protein changes.
|
|
