Lassitermccarty6522

A central quantity of interest in molecular biology and medicine is the free energy of binding of a molecule to a target biomacromolecule. Until recently, the accurate prediction of binding affinity had been widely regarded as out of reach of theoretical methods owing to the lack of reproducibility of the available methods, not to mention their complexity, computational cost and time-consuming procedures. The lack of reproducibility stems primarily from the chaotic nature of classical molecular dynamics (MD) and the associated extreme sensitivity of trajectories to their initial conditions. Here, we review computational approaches for both relative and absolute binding free energy calculations, and illustrate their application to a diverse set of ligands bound to a range of proteins with immediate relevance in a number of medical domains. We focus on ensemble-based methods which are essential in order to compute statistically robust results, including two we have recently developed, namely thermodynamic integration with enhanced sampling and enhanced sampling of MD with an approximation of continuum solvent. Together, these form a set of rapid, accurate, precise and reproducible free energy methods. They can be used in real-world problems such as hit-to-lead and lead optimization stages in drug discovery, and in personalized medicine. These applications show that individual binding affinities equipped with uncertainty quantification may be computed in a few hours on a massive scale given access to suitable high-end computing resources and workflow automation. A high level of accuracy can be achieved using these approaches.Computational methods are the most effective tools we have besides scientific experiments to explore the properties of complex biological systems. Progress is slowing because digital silicon computers have reached their limits in terms of speed. Other types of computation using radically different architectures, including neuromorphic and quantum, promise breakthroughs in both speed and efficiency. Quantum computing exploits the coherence and superposition properties of quantum systems to explore many possible computational paths in parallel. This provides a fundamentally more efficient route to solving some types of computational problems, including several of relevance to biological simulations. In particular, optimization problems, both convex and non-convex, feature in many biological models, including protein folding and molecular dynamics. Early quantum computers will be small, reminiscent of the early days of digital silicon computing. Understanding how to exploit the first generation of quantum hardware is crucial for making progress in both biological simulation and the development of the next generations of quantum computers. This review outlines the current state-of-the-art and future prospects for quantum computing, and provides some indications of how and where to apply it to speed up bottlenecks in biological simulation.The emergence of antimicrobial resistance threatens modern medicine and necessitates more personalized treatment of bacterial infections. Sequencing the whole genome of the pathogen(s) in a clinical sample offers one way to improve clinical microbiology diagnostic services, and has already been adopted for tuberculosis in some countries. A key weakness of a genetics clinical microbiology is it cannot return a result for rare or novel genetic variants and therefore predictive methods are required. Non-synonymous mutations in the S. aureusdfrB gene can be successfully classified as either conferring resistance (or not) by calculating their effect on the binding free energy of the antibiotic, trimethoprim. The underlying approach, alchemical free energy methods, requires large numbers of molecular dynamics simulations to be run. We show that a large number (N = 15) of binding free energies calculated from a series of very short (50 ps) molecular dynamics simulations are able to satisfactorily classify all seven mutations in our clinically derived testset. A result for a single mutation could therefore be returned in less than an hour, thereby demonstrating that this or similar methods are now sufficiently fast and reproducible for clinical use.In recent years, it has become possible to calculate binding affinities of compounds bound to proteins via rapid, accurate, precise and reproducible free energy calculations. This is imperative in drug discovery as well as personalized medicine. This approach is based on molecular dynamics (MD) simulations and draws on sequence and structural information of the protein and compound concerned. Free energies are determined by ensemble averages of many MD replicas, each of which requires hundreds of cores and/or GPU accelerators, which are now available on commodity cloud computing platforms; there are also requirements for initial model building and subsequent data analysis stages. Angiogenesis chemical To automate the process, we have developed a workflow known as the binding affinity calculator. In this paper, we focus on the software infrastructure and interfaces that we have developed to automate the overall workflow and execute it on commodity cloud platforms, in order to reliably predict their binding affinities on time scales relevant to the domains of application, and illustrate its application to two free energy methods.We apply the hit-to-lead ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and lead-optimization TIES (thermodynamic integration with enhanced sampling) methods to compute the binding free energies of a series of ligands at the A1 and A2A adenosine receptors, members of a subclass of the GPCR (G protein-coupled receptor) superfamily. Our predicted binding free energies, calculated using ESMACS, show a good correlation with previously reported experimental values of the ligands studied. Relative binding free energies, calculated using TIES, accurately predict experimentally determined values within a mean absolute error of approximately 1 kcal mol-1. Our methodology may be applied widely within the GPCR superfamily and to other small molecule-receptor protein systems.