Variational Methods for Biomolecular Modeling

Structure, function and dynamics of many biomolecular systems can be characterized by the energetic variational principle and the corresponding systems of partial differential equations (PDEs). This principle allows us to focus on the identification of essential energetic components, the optimal parametrization of energies, and the efficient computational implementation of energy variation or minimization. Given the fact that complex biomolecular systems are structurally non-uniform and their interactions occur through contact interfaces, their free energies are associated with various interfaces as well, such as solute-solvent interface, molecular binding interface, lipid domain interface, and membrane surfaces. This fact motivates the inclusion of interface geometry, particular its curvatures, to the parametrization of free energies. Applications of such interface geometry based energetic variational principles are illustrated through three concrete topics: the multiscale modeling of biomolecular electrostatics and solvation that includes the curvature energy of the molecular surface, the formation of microdomains on lipid membrane due to the geometric and molecular mechanics at the lipid interface, and the mean curvature driven protein localization on membrane surfaces. By further implicitly representing the interface using a phase field function over the entire domain, one can simulate the dynamics of the interface and the corresponding energy variation by evolving the phase field function, achieving significant reduction of the number of degrees of freedom and computational complexity. Strategies for improving the efficiency of computational implementations and for extending applications to coarse-graining or multiscale molecular simulations are outlined.Comment: 36 page

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID

A review of methods for the calculation of solution free energies and the modelling of systems in solution

JLMcD and JBOM are grateful to SULSA for funding; RES and JBOM thank the University of St Andrews, EPSRC (grant EP/L505079/1) and CCDC for funding.Over the past decade, pharmaceutical companies have seen a decline in the number of drug candidates successfully passing through clinical trials, though billions are still spent on drug development. Poor aqueous solubility leads to low bio-availability, reducing pharmaceutical effectiveness. The human cost of inefficient drug candidate testing is of great medical concern, with fewer drugs making it to the production line, slowing the development of new treatments. In biochemistry and biophysics, water mediated reactions and interactions within active sites and protein pockets are an active area of research, in which methods for modelling solvated systems are continually pushed to their limits. Here, we discuss a multitude of methods aimed towards solvent modelling and solubility prediction, aiming to inform the reader of the options available, and outlining the various advantages and disadvantages of each approach.Publisher PDFPeer reviewe

A review of methods for the calculation of solution free energies and the modelling of systems in solution

Over the past decade, pharmaceutical companies have seen a decline in the number of drug candidates successfully passing through clinical trials, though billions are still spent on drug development. Poor aqueous solubility leads to low bio-availability, reducing pharmaceutical effectiveness. The human cost of inefficient drug candidate testing is of great medical concern, with fewer drugs making it to the production line, slowing the development of new treatments. In biochemistry and biophysics, water mediated reactions and interactions within active sites and protein pockets are an active area of research, in which methods for modelling solvated systems are continually pushed to their limits. Here, we discuss a multitude of methods aimed towards solvent modelling and solubility prediction, aiming to inform the reader of the options available, and outlining the various advantages and disadvantages of each approach

Crystal Structures of SARS-CoV-2 main protease with screening fragments and COVID Moonshot compounds from the XChem facility at Diamond Light Source

<p>Bulk repositiory of structures of SARS-CoV-2 main protease in complex with fragment molecules from inital XChem screen and designed COVID Moonshot inhibtor compounds. Each structure has a PDB ID, coordinate file, structure factor file, ligand restraint (cif) and PANDDA event maps (as appropriate).</p><p>2023-10-26 - updated to include <strong>all </strong>initial fragment screening hits alongside follow up compounds</p&gt

Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors