Characterizing Protein-Protein Interactions with the Fragment Molecular Orbital Method

Proteins are vital components of living systems, serving as building blocks, molecular machines, enzymes, receptors, ion channels, sensors, and transporters. Protein-protein interactions (PPIs) are a key part of their function. There are more than 645,000 reported disease-relevant PPIs in the human interactome, but drugs have been developed for only 2% of these targets. The advances in PPI-focused drug discovery are highly dependent on the availability of structural data and accurate computational tools for analysis of this data. Quantum mechanical approaches are often too expensive computationally, but the fragment molecular orbital (FMO) method offers an excellent solution that combines accuracy, speed and the ability to reveal key interactions that would otherwise be hard to detect. FMO provides essential information for PPI drug discovery, namely, identification of key interactions formed between residues of two proteins, including their strength (in kcal/mol) and their chemical nature (electrostatic or hydrophobic). In this chapter, we have demonstrated how three different FMO-based approaches (pair interaction energy analysis (PIE analysis), subsystem analysis (SA) and analysis of protein residue networks (PRNs)) have been applied to study PPI in three protein-protein complexes

Measuring change in trials of physical activity interventions: a comparison of self-report questionnaire and accelerometry within the PACE-UP trial

Background: Few trials have compared estimates of change in physical activity (PA) levels using self-reported and objective PA measures when evaluating trial outcomes. The PACE-UP trial offered the opportunity to assess this, using the self-administered International Physical Activity Questionnaire (IPAQ) and waist-worn accelerometry. Methods: The PACE-UP trial (N=1023) compared usual care (n=338) with two pedometer-based walking interventions, by post (n=339) or with nurse support (n=346). Participants wore an accelerometer at baseline and 12months and completed IPAQ for the same 7-day periods. Main outcomes were weekly minutes, all in ≥10min bouts as per UK PA guidelines of: i) accelerometer moderate-to-vigorous PA (Acc-MVPA) ii) IPAQ moderate+vigorous PA (IPAQ-MVPA) and iii) IPAQ walking (IPAQ-Walk). For each outcome, 12month values were regressed on baseline to estimate change. Results: Analyses were restricted to 655 (64%) participants who provided data on all outcomes at baseline and 12 months. Both intervention groups significantly increased their accelerometry MVPA minutes/week compared with control: postal group 42 (95% CI 22, 61), nurse group 43 (95% CI 24, 63). IPAQ-Walk minutes/week also increased: postal 57 (95% CI 2, 112), nurse 43 (95% CI -11, 97) but IPAQ-MVPA minutes/week showed non-significant decreases: postal -11 (95% CI -65, 42), nurse -34 (95% CI -87, 19). Conclusions: Our results demonstrate the necessity of using a questionnaire focussing on the activities being altered, as with IPAQ-Walk questions. Even then, the change in PA was estimated with far less precision than with accelerometry. Accelerometry is preferred to self-report measurement, minimising bias and improving precision when assessing effects of a walking intervention

Older adults\u27 quality of life - exploring the role of the built environment and social cohesion in community-dwelling seniors on low income

The built environment and social cohesion are increasingly recognized as being associated with older adults\u27 quality of life (QoL). However, limited research in this area still exists and the relationship has remained unexplored in the area of Metro Vancouver, Canada. This study examined the association between the built environment and social cohesion with QoL of 160 community-dwelling older adults (aged ≥ 65 years) on low income from Metro Vancouver. Cross-sectional data acquired from the Walk the Talk (WTT) study were used. Health-related QoL (HRQoL) and capability wellbeing were assessed using the EQ-5D-5L and the ICECAP-O, respectively. Measures of the environment comprised the NEWS-A (perceived built environment measure), the Street Smart Walk Score (objective built environment measure), and the SC-5PT (a measure of social cohesion). The primary analysis consists of Tobit regression models to explore the associations between environmental features and HRQoL as well as capability wellbeing. Key findings indicate that after adjusting for covariates, older adults\u27 capability wellbeing was associated with street connectivity and social cohesion, while no statistically significant associations were found between environmental factors and HRQoL. Our results should be considered as hypothesis-generating and need confirmation in a larger longitudinal study

Promotion of physical activity for older people with musculoskeletal conditions

Many older adults have musculoskeletal conditions that can act as a substantial barrier to physical activity. Older people, and some health professionals, may be concerned that participating in exercise programmes or completing other physical activities may cause or exacerbate symptoms associated with existing musculoskeletal conditions. However, in most cases, there are safe exercise-based interventions that have potential to improve function and general health without undue risk. This chapter discusses several groups of musculoskeletal conditions that are prevalent among older adults and provides a practical case study as well as some points for broader consideration