Changes in pain and disability in patients with shoulder pain after three months of digitally delivered exercise and patient education.

OBJECTIVE: To describe and examine potential predictors of changes in pain and disability in patients with shoulder pain who have completed 3 months of digitally delivered treatment comprising exercise and patient education. DESIGN: Retrospective cohort study (clinicaltrials.org Nr: NCT05402514). SUBJECTS: Patients with shoulder pain who completed treatment (n = 682). METHODS: Primary outcome was change in shoulder pain (numerical rating scale 0-10; minimal clinical important change: at least 2 points). Pain and disability were reported on the Shoulder Pain and Disability Index. Changes in outcomes were analysed with paired sample t-tests. Association with potential predictors (sex, age, education, body mass index, physical activity, symptom duration, baseline pain/function, and treatment adherence) were explored with linear regression models Results: Statistically significant improvements were found for all treatment outcomes. Minimal clinically important change in pain was reached by 54.5% (n = 372). Higher baseline level of symptoms, short symptom duration, and high treatment adherence were associated with greater changes. CONCLUSION: Patients with shoulder pain reported significant reductions in pain and disability following treatment, but the clinical relevance of the improvements has not been confirmed. Satisfactory treatment adherence, higher baseline pain and shorter symptom duration predicted larger improvements. A control group is needed to evaluate the actual effect of the treatment.

Digitally Delivered Exercise and Education Treatment Program for Low Back Pain: Longitudinal Observational Cohort Study.

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. TRIAL REGISTRATION: ClinicalTrials.gov NCT05226156; https://clinicaltrials.gov/ct2/show/NCT05226156.

Comparison of Grand Canonical and Conventional Molecular Dynamics Simulation Methods for Protein-Bound Water Networks.

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.

Water structure in solution and crystal molecular dynamics simulations compared to protein crystal structures.

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.

Substituted polyfluoroaryl interactions with an arginine side chain in galectin-3 are governed by steric-, desolvation and electronic conjugation effects.

In the ß-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.

Binding free energies in the SAMPL6 octa-acid host-guest challenge calculated with MM and QM methods.

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.

Can MM/GBSA calculations be sped up by system truncation?

We have studied whether calculations of the binding free energy of small ligands to a protein by the MM/GBSA approach (molecular mechanics combined with generalized Born and surface area solvation) can be sped up by including only a restricted number of atoms close to the ligand. If the protein is truncated before the molecular dynamics (MD) simulations, quite large changes are observed for the calculated binding energies, for example, 4 kJ/mol average difference for a radius of 19 Å for the binding of nine phenol derivatives to ferritin. The results are improved if no atoms are fixed in the simulations, with average and maximum errors of 2 and 3 kJ/mol at 19 Å and 3 and 6 kJ/mol at 7 Å. Similar results are obtained for two additional proteins, p38α MAP kinase and factor Xa. On the other hand, if energies are calculated on snapshots that are truncated after the MD simulation, all residues more than 8.5 Å from the ligand can be omitted without changing the energies by more than 1 kJ/mol on average (maximum error 1.4 kJ/mol). At the molecular mechanics level, the gain in computer time for such an approach is small. However, it shows what size of system should be used if the energies instead are calculated with a more demanding method, for example, quantum-mechanics. © 2017 Wiley Periodicals, Inc.

Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations.

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.

Hydrogen Bonding between Metal-Ion Complexes and Noncoordinated Water: Electrostatic Potentials and Interaction Energies.

The hydrogen bonding of noncoordinated water molecules to each other and to water molecules that are coordinated to metal-ion complexes has been investigated by means of a search of the Cambridge Structural Database (CSD) and through quantum chemical calculations. Tetrahedral and octahedral complexes that were both charged and neutral were studied. A general conclusion is that hydrogen bonds between noncoordinated water and coordinated water are much stronger than those between noncoordinated waters, whereas hydrogen bonds of water molecule in tetrahedral complexes are stronger than in octahedral complexes. We examined the possibility of correlating the computed interaction energies with the most positive electrostatic potentials on the interacting hydrogen atoms prior to interaction and obtained very good correlation. This study illustrates the fact that electrostatic potentials computed for ground-state molecules, prior to interaction, can provide considerable insight into the interactions.