Biology subjects

Harris, B. J.

Publications and source records attributed to Harris, B. J..

3 recordsLinked to original sources

bioRxiv2024

Towards high-resolution modeling of small molecule-ion channel interactions

Ion channels are critical drug discovery targets for a wider range of pathologies, such as epilepsy, chronic pain, itch, autoimmunity, and cardiac arrhythmias. To develop effective and safe therapeutics, it is necessary to design small molecules with high potency and selectivity for specific ion channel subtypes. There has been increasing implementation of structure-guided drug design for the development of small molecules targeting ion channels. We evaluated the performance of two Rosetta ligand docking methods, RosettaLigand and GALigandDock, on structures of known ligand - cation channel complexes. Ligands were docked to voltage-gated sodium (NaV), voltage-gated calcium (CaV), and transient receptor potential vanilloid (TRPV) channel families. For each test case, RosettaLigand and GALigandDock methods were able to frequently sample a ligand binding pose within 1-2 [A] root mean square deviation (RMSD) relative to the native ligand - channel structure. However, RosettaLigand and GALigandDock scoring functions cannot consistently identify native drug binding poses as top-scoring models. Our study reveals that the proper scoring criteria for RosettaLigand and GALigandDock modeling of ligand - ion channel complexes should be assessed on a case-by-case basis using sufficient ligand and receptor interface sampling, knowledge about state specific interactions of the ion channel and inherent receptor site flexibility that could influence ligand binding.

biophysics↗

bioRxiv2022

Simulated docking reveals putative channels for the transport of long-chain fatty acids in Vibrio cholerae

Fatty acids (FA) play an important role in biological functions, such as membrane homeostasis, metabolism, and as signaling molecules. FadL is the only known protein that uptakes long-chain fatty acids in Gram-negative bacteria, and this uptake has traditionally been thought to be limited to fatty acids up to 18 carbon atoms in length. Recently however, it was found Vibrio cholerae has the ability to uptake fatty acids greater than 18 carbon atoms and this uptake corresponds to higher bacterial survivability. Using E. colis FadL as a template, V. cholerae FadL homologs vc1042, vc1043, and vca0862 have been folded, simulated on an atomistic level using molecular dynamics, and analyzed revealing the FadL transport channels. For vc1042 and vc1043 these transport channels have more structural accommodations for the many rigid unsaturated bonds of long-chain polyunsaturated fatty acids, while vca0862 was found to lack transport channels within the signature beta barrel of FadL proteins. IMPORTANCEFatty acids are important precursors for membrane phospholipids as well as energy sources for bacteria. V. choleraes uptake of long-chain fatty acids has not been studied to the atomistic level at this point, and by doing so, the resulting putative pathways show important structural details of the transport protein. Not only do the transport channels have unique differences between one another, the predicted transport mechanics of V. choleraes protein homologs differ substantially from the E. coli FadLs pathway found from X-ray crystallography studies.

molecular biology↗

bioRxiv2021

Divergent evolutionary trajectories of bryophytes and tracheophytes from a complex common ancestor of land plants

The origin of plants and their colonization of land resulted in the transformation of the terrestrial environment. Here we investigate the evolution of the land plants (embryophytes) and their two main lineages, the tracheophytes (vascular plants) and bryophytes (non-vascular plants). We used new fossil calibrations, relative lineage dating implied by horizontal gene transfer, and new phylogenomic methods for mapping gene family origins. Distinct rooting strategies resolve tracheophytes and bryophytes as monophyletic sister groups that diverged during the Cambrian, 515-494 Ma. The embryophyte stem is characterised by a burst of gene innovation, while bryophytes subsequently experienced a no less dramatic episode of reductive genome evolution in which they lost genes associated with the elaboration of vasculature and the stomatal complex. Overall, our analyses confirm that extant tracheophytes and bryophytes are both highly derived; as a result, understanding the origin of land plants requires tracing character evolution across the diversity of modern lineages.

evolutionary biology↗