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453 Publications visible to you, out of a total of 453
P. falciparum Circumsporozoite protein epitope/paratope interactions: Addressing the key role of molecular flexibility

Abstract

Not specified

Author: Anton Hanke

Date Published: 2022

Publication Type: Master's Thesis

Structural Insights into Neurotrophin Receptor Dimerization using Coarse-grained Molecular Dynamics Simulations

Abstract

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Author: Ainara Claveras Cabezudo

Date Published: 2022

Publication Type: Master's Thesis

Multiscale Approach for Computing Gated Ligand Binding from Molecular Dynamics and Brownian Dynamics Simulations

Abstract

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Authors: S. Kashif Sadiq, Abraham Muñiz Chicharro, Patrick Friedrich, Rebecca C. Wade

Date Published: 14th Dec 2021

Publication Type: Journal

An electron transfer competent structural ensemble of membrane-bound cytochrome P450 1A1 and cytochrome P450 oxidoreductase

Abstract (Expand)

Abstract Cytochrome P450 (CYP) heme monooxygenases require two electrons for their catalytic cycle. For mammalian microsomal CYPs, key enzymes for xenobiotic metabolism and steroidogenesis and important …roidogenesis and important drug targets and biocatalysts, the electrons are transferred by NADPH-cytochrome P450 oxidoreductase (CPR). No structure of a mammalian CYP–CPR complex has been solved experimentally, hindering understanding of the determinants of electron transfer (ET), which is often rate-limiting for CYP reactions. Here, we investigated the interactions between membrane-bound CYP 1A1, an antitumor drug target, and CPR by a multiresolution computational approach. We find that upon binding to CPR, the CYP 1A1 catalytic domain becomes less embedded in the membrane and reorients, indicating that CPR may affect ligand passage to the CYP active site. Despite the constraints imposed by membrane binding, we identify several arrangements of CPR around CYP 1A1 that are compatible with ET. In the complexes, the interactions of the CPR FMN domain with the proximal side of CYP 1A1 are supplemented by more transient interactions of the CPR NADP domain with the distal side of CYP 1A1. Computed ET rates and pathways agree well with available experimental data and suggest why the CYP–CPR ET rates are low compared to those of soluble bacterial CYPs.

Authors: Goutam Mukherjee, Prajwal P. Nandekar, Rebecca C. Wade

Date Published: 1st Dec 2021

Publication Type: Journal

Putative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s disease

Abstract (Expand)

Abstract Rare variants in the beta-glucocerebrosidase gene ( GBA1 ) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease …hich often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.

Authors: Muhammad Aslam, Nirosiya Kandasamy, Anwar Ullah, Nagarajan Paramasivam, Mehmet Ali Öztürk, Saima Naureen, Abida Arshad, Mazhar Badshah, Kafaitullah Khan, Muhammad Wajid, Rashda Abbasi, Muhammad Ilyas, Roland Eils, Matthias Schlesner, Rebecca C. Wade, Nafees Ahmad, Jakob von Engelhardt

Date Published: 1st Dec 2021

Publication Type: Journal

Contact Map Fingerprints of Protein–Ligand Unbinding Trajectories Reveal Mechanisms Determining Residence Times Computed from Scaled Molecular Dynamics

Abstract

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Authors: Marc Bianciotto, Paraskevi Gkeka, Daria B. Kokh, Rebecca C. Wade, Hervé Minoux

Date Published: 12th Oct 2021

Publication Type: Journal

G Protein-Coupled Receptor–Ligand Dissociation Rates and Mechanisms from τRAMD Simulations

Abstract

Not specified

Authors: Daria B. Kokh, Rebecca C. Wade

Date Published: 12th Oct 2021

Publication Type: Journal

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