Using advanced computational methods to model the binding of antibody complexes: a case study from the coagulation cascade

Haemophilia A is a congenital bleeding disorder affecting one in 5,000 to 10,000 males. To prevent symptomatic disease, injections of recombinant factor VIII (FVIII) are administered to compensate for insufficient levels of this essential clotting factor. Patients suffering from a severe form of haemophilia A are at increased risk of forming neutralising antibodies — known as inhibitors — against therapeutic FVIII. A better understanding of the binding characteristics of inhibitors may aid the selection of optimal haemophilia A therapies, lead to the development of new therapeutics that are less antigenic, and support future initiatives in personalised and precision medicine. With this goal in mind, Classical Molecular Dynamics (CMD) in conjunction with Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) free energy calculations, together with enhanced sampling techniques, have been used to investigate interactions and the dynamics of binding site residues of the human inhibitory antibody BO2C11 bound to the C2-domain of factor VIII. In parallel, recombinant bacterial expressions of the C2-domain were initiated with the aim to explore structural changes induced by mutations that abrogate binding as described previously in surface plasmon resonance experiments. Computational binding affinity predictions were generally shown to be in good agreement with experimental findings. Additionally, binding site dynamics were investigated in detail using customized visualization techniques and an interpretable machine learning approach. Nevertheless, CMD simulations were insufficient for gaining insights into structural changes induced by mutations that were determined experimentally to be non-binding, and for exploring the underlying differences between the bound and unbound structures of the FVIII-C2 domain. To this end, Accelerated Molecular Dynamics (AMD) and Umbrella Sampling (US) simulations proved to be appropriate additions to investigate the conformational changes and energetic differences associated with the binding of BO2C11

BMI, Psychosocial Correlates, Pain and Activities of Daily Living in Sickle Cell Disease Patients

Pain, psychosocial issues and impaired activities of daily living (ADLs) are common in sickle cell disease (SCD). Improved longevity may be leading to increases in body mass index (BMI). We both describe an SCD clinic population and determine if BMI, psychosocial distress, and pain predict impairments in ADLs. Archival data from 252 adult African American SCD clinic patients were examined (ie gender, BMI, SCD type, psychosocial status via Symptom Checklist-90-Revised; pain via Short-form McGill Pain Questionnaire: Sensory Pain, Affective Pain (AP), Present Pain Intensity and ADLs. In total, 44% of the sample was overweight (BMI ≥ 25 kg/m2). Depression, anxiety, and Symptom Checklist-90-Revised Global Severity Index were in the clinical range. Patients with HbSβ+-thalassemia and hemoglobin SC disease had higher BMIs than those with HbSS (P < 0.001). AP and age-predicted impaired ADLs. In an OW/OB subsample, AP, age, and SCD severity predicted impaired ADLs. The consistent relationship of AP to ADL impairment suggests targeting AP via behavioral pain management may improve functioning