Development of a united-atom protein model coupled with a coarse-grained solvent model for biomolecular simulation

Protein modeling with molecular mechanics force fields plays an important role in computational biology. However, handling real systems with the current popular all-atom force fields is limited in both size and timescale due to the computationally demanding nature of these force fields. One of the solutions is to use coarse-grained (CG) force field. This thesis reports our effort to develop a new CG force field for biomolecular simulations. To retain the high accuracy that all-atom force fields possess, we use united-atom model to represent each amino acid residue. The solvent model is coarse-grained, with four water molecules represented by one van der Waals particle, so that the simulation speed can be greatly enhanced. Chapter 2 reports the parameterization work for protein-protein and protein-water interactions. Densities and self-solvation free energies of eight pure organic liquids were well reproduced. We could also accurately reproduce the hydration free energies of 105 small organic compounds with an average absolute error of 1.4 kJ/mol. Chapter 3 reports the optimization of backbone and side-chain dihedral parameters and parameterization of protein polar-polar interactions. We show in chapter 4 that this force field is able to fold α-helical, β-sheet and mixed helical/coil peptides. Chapter 5 reports the work for the extension of the force field to study transmembrane peptides. We studied the association of two glycophorin A helices. Our force field gave the best simulated dimer structure so far by current CG force fields. This work demonstrates the high accuracy and applicability of the new force field for biomolecular simulations

Parameterization of PACE Force Field for Membrane Environment and Simulation of Helical Peptides and Helix–Helix Association

The recently developed PACE force field was further parametrized so that it can be applied to the studies of membrane systems. Parameters for the interactions between united-atom protein particles and lipid hydrophobic tails were developed by reproducing the solvation free energies of small organic molecules in hexadecane. Interactions between protein particles and lipid heads were parametrized by fitting the potential of mean force of the corresponding all-atom simulation. The force field was applied to the study of five helical peptides in membrane environments. The calculated tilt angles of WALP and GWALP and their mutations are in good agreement with experimental data. The association of two glycophorin A (GpA) helices was simulated for 6 μs. Root-mean-square-deviation of the simulated dimer from the nuclear magnetic resonance structure was found to be 0.272 nm, better than all results obtained so far. These findings demonstrate the high accuracy and applicability of the PACE force field in studying membrane proteins

Immune-Related Endocrine Dysfunctions in Combined Modalities of Treatment: Real-World Data

The number of immune-related endocrine dysfunctions (irEDs) has concurrently increased with the widespread use of immunotherapy in clinical practice and further expansion of the approved indications for immune checkpoint inhibitor (ICI) in cancer management. A retrospective analysis was conducted on consecutive patients ≥18 years of age with advanced solid malignancies who had received at least one dose of anti-programmed cell death protein 1 (anti-PD-1) and/or anti-CTLA4 antibodies between January 2014 and December 2019 at a university hospital in Hong Kong. Patients were reviewed up to two months after the last administration of an ICI. The types, onset times and grades of irEDs, including hypothyroidism, hyperthyroidism, adrenal insufficiency and immune-related diabetes mellitus, were recorded. Factors associated with irEDs were identified using multivariate analysis. A total of 953 patients (male: 603, 64.0%; median age: 62.0 years) were included. Of these, 580 patients (60.9%) used ICI-alone, 132 (13.9%) used dual-ICI, 187 (19.6%) used an ICI combined with chemotherapy (chemo + ICI), and 54 (5.70%) used immunotherapy with a targeted agent (targeted + ICI). A significantly higher proportion of patients using targeted + ICI had irEDs and hypothyroidism; in contrast, a higher proportion of patients using dual-ICI had adrenal insufficiency. There was no significant difference in the incidence of irED between the younger (<65 years) and older (≥65 years) patients. Using logistic regression, only treatment type was significantly associated with irEDs. Notably, older patients had a higher risk of having immune-related diabetes mellitus. This large, real-world cohort demonstrates that targeted + ICI has a higher risk of overall irED and hypothyroidism. Immunotherapy is safe and well-tolerated regardless of age, but close monitoring of fasting glucose is essential in older populations

Mitochondrial diseases in Hong Kong: prevalence, clinical characteristics and genetic landscape

Abstract Objective To determine the prevalence of mitochondrial diseases (MD) in Hong Kong (HK) and to evaluate the clinical characteristics and genetic landscape of MD patients in the region. Methods This study retrospectively reviewed the phenotypic and molecular characteristics of MD patients from participating public hospitals in HK between January 1985 to October 2020. Molecularly and/or enzymatically confirmed MD cases of any age were recruited via the Clinical Analysis and Reporting System (CDARS) using relevant keywords and/or International Classification of Disease (ICD) codes under the HK Hospital Authority or through the personal recollection of treating clinicians among the investigators. Results A total of 119 MD patients were recruited and analyzed in the study. The point prevalence of MD in HK was 1.02 in 100,000 people (95% confidence interval 0.81–1.28 in 100,000). 110 patients had molecularly proven MD and the other nine were diagnosed by OXPHOS enzymology analysis or mitochondrial DNA depletion analysis with unknown molecular basis. Pathogenic variants in the mitochondrial genome (72 patients) were more prevalent than those in the nuclear genome (38 patients) in our cohort. The most commonly involved organ system at disease onset was the neurological system, in which developmental delay, seizures or epilepsy, and stroke-like episodes were the most frequently reported presentations. The mortality rate in our cohort was 37%. Conclusion This study is a territory-wide overview of the clinical and genetic characteristics of MD patients in a Chinese population, providing the first available prevalence rate of MD in Hong Kong. The findings of this study aim to facilitate future in-depth evaluation of MD and lay the foundation to establish a local MD registry

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially