Differential performance of RoseTTAFold in antibody modeling.

Antibodies are essential to life, and knowing their structures can facilitate the understanding of antibody-antigen recognition mechanisms. Precise antibody structure prediction has been a core challenge for a prolonged period, especially the accuracy of H3 loop prediction. Despite recent progress, existing methods cannot achieve atomic accuracy, especially when the homologous structures required for these methods are not available. Recently, RoseTTAFold, a deep learning-based algorithm, has shown remarkable breakthroughs in predicting the 3D structures of proteins. To assess the antibody modeling ability of RoseTTAFold, we first retrieved the sequences of 30 antibodies as the test set and used RoseTTAFold to model their 3D structures. We then compared the models constructed by RoseTTAFold with those of SWISS-MODEL in a different way, in which we stratified Global Model Quality Estimate (GMQE) into three different ranges. The results indicated that RoseTTAFold could achieve results similar to SWISS-MODEL in modeling most CDR loops, especially the templates with a GMQE score under 0.8. In addition, we also compared the structures modeled by RoseTTAFold, SWISS-MODEL and ABodyBuilder. In brief, RoseTTAFold could accurately predict 3D structures of antibodies, but its accuracy was not as good as the other two methods. However, RoseTTAFold exhibited better accuracy for modeling H3 loop than ABodyBuilder and was comparable to SWISS-MODEL. Finally, we discussed the limitations and potential improvements of the current RoseTTAFold, which may help to further the accuracy of RoseTTAFold's antibody modeling.

Molecular Modeling Study of a Receptor-Orthosteric Ligand-Allosteric Modulator Signaling Complex.

Allosteric modulators (AMs) are considered as a perpetual hotspot in research for their higher selectivity and various effects on orthosteric ligands (OL). They are classified in terms of their functionalities as positive, negative, or silent allosteric modulators (PAM, NAM, or SAM, respectively). In the present work, 11 pairs of three-dimensional (3D) structures of receptor-orthosteric ligand and receptor-orthosteric ligand-allosteric modulator complexes have been collected for the studies, including three different systems: GPCR, enzyme, and ion channel. Molecular dynamics (MD) simulations are applied to quantify the dynamic interactions in both the orthosteric and allosteric binding pockets and the structural fluctuation of the involved proteins. Our results showed that MD simulations of moderately large molecules or peptides undergo insignificant changes compared to crystal structure results. Furthermore, we also studied the conformational changes of receptors that bound with PAM and NAM, as well as the different allosteric binding sites in a receptor. There should be no preference for the position of the allosteric binding pocket after comparing the allosteric binding pockets of these three systems. Finally, we aligned four distinct ß2 adrenoceptor structures and three N-methyl-d-aspartate receptor (NMDAR) structures to investigate conformational changes. In the ß2 adrenoceptor systems, the aligned results revealed that transmembrane (TM) helices 1, 5, and 6 gradually increased outward movement from an enhanced inactive state to an improved active state. TM6 endured the most significant conformational changes (around 11 Å). For NMDAR, the bottom section of NMDAR's ligand-binding domain (LBD) experienced an upward and outward shift during the gradually activating process. In conclusion, our research provides insight into receptor-orthosteric ligand-allosteric modulator studies and the design and development of allosteric modulator drugs using MD simulation.

Virus-CKB 2.0: Viral-Associated Disease-Specific Chemogenomics Knowledgebase.

Transmissible and infectious viruses can cause large-scale epidemics around the world. This is because the virus can constantly mutate and produce different variants and subvariants to counter existing treatments. Therefore, a variety of treatments are urgently needed to keep up with the mutation of the viruses. To facilitate the research of such treatment, we updated our Virus-CKB 1.0 to Virus-CKB 2.0, which contains 10 kinds of viruses, including enterovirus, dengue virus, hepatitis C virus, Zika virus, herpes simplex virus, Andes orthohantavirus, human immunodeficiency virus, Ebola virus, Lassa virus, influenza virus, coronavirus, and norovirus. To date, Virus-CKB 2.0 archived at least 65 antiviral drugs (such as remdesivir, telaprevir, acyclovir, boceprevir, and nelfinavir) in the market, 178 viral-related targets with 292 available 3D crystal or cryo-EM structures, and 3766 chemical agents reported for these target proteins. Virus-CKB 2.0 is integrated with established tools for target prediction and result visualization; these include HTDocking, TargetHunter, blood-brain barrier (BBB) predictor, Spider Plot, etc. The Virus-CKB 2.0 server is accessible at https://www.cbligand.org/g/virus-ckb. By using the established chemogenomic tools and algorithms and newly developed tools, we can screen FDA-approved drugs and chemical compounds that may bind to these proteins involved in viral-associated disease regulation. If the virus strain mutates and the vaccine loses its effect, we can still screen drugs that can be used to treat the mutated virus in a fleeting time. In some cases, we can even repurpose FDA-approved drugs through Virus-CKB 2.0.

Assessment of anxiety and depression after lower limb amputation in Jordanian patients.

OBJECTIVE: This study aimed to assess the prevalence of anxiety and depression among Jordanian lower limb amputees with different clinical characteristics and sociodemographic data (gender, marital status, social support, income, type and level of amputation, and occupation). METHODS: Participants were 56 patients with unilateral lower limb amputation with mean duration (8.4 +/- 5.75 years). They were recruited from inpatient and outpatient clinics of Jordan University hospital, Royal Farah Rehabilitation Center, and Al-basheer hospital in Amman, Jordan. Participants responded to a questionnaire that included a battery of questions requesting brief information about sociodemographic variables and characteristics of amputation. The level of depression and anxiety in each participating patient was assessed by the Hospital Anxiety and Depression Scale (HADS). RESULTS: The prevalence of anxiety and depressive symptoms were 37% and 20%, respectively. Factors associated with high prevalence of psychological symptoms included female gender, lack of social support, unemployment, traumatic amputation, shorter time since amputation, and amputation below the knee. These findings were confirmed by a significant reduction of anxiety and depression scores in patients who received social support, patients with amputation due to disease, and patients with amputation above the knee. Presence of pain and use of prosthesis had no effect on the prevalence. CONCLUSIONS: The findings of the present study highlight the high incidence of psychiatric disability and depression in amputees; it also showed the importance of sociodemographic factors in psychological adjustment to amputation. It is suggested that psychiatric evaluation and adequate rehabilitation should form a part of their overall management.