RESUMO
Urban climate model evaluation often remains limited by a lack of trusted urban weather observations. The increasing density of personal weather sensors (PWSs) make them a potential rich source of data for urban climate studies that address the lack of representative urban weather observations. In our study, we demonstrate that carefully quality-checked PWS data not only improve urban climate models' evaluation but can also serve for bias correcting their output prior to any urban climate impact studies. After simulating near-surface air temperatures over London and south-east England during the hot summer of 2018 with the Weather Research and Forecasting (WRF) Model and its building Effect parameterization with the building energy model (BEP-BEM) activated, we evaluated the modeled temperatures against 402 urban PWSs and showcased a heterogeneous spatial distribution of the model's cool bias that was not captured using official weather stations only. This finding indicated a need for spatially explicit urban bias corrections of air temperatures, which we performed using an innovative method using machine learning to predict the models' biases in each urban grid cell. This bias-correction technique is the first to consider that modeled urban temperatures follow a nonlinear spatially heterogeneous bias that is decorrelated from urban fraction. Our results showed that the bias correction was beneficial to bias correct daily minimum, daily mean, and daily maximum temperatures in the cities. We recommend that urban climate modelers further investigate the use of quality-checked PWSs for model evaluation and derive a framework for bias correction of urban climate simulations that can serve urban climate impact studies.
RESUMO
The use of molecular simulation to estimate the strength of macromolecular binding free energies is becoming increasingly widespread, with goals ranging from lead optimization and enrichment in drug discovery to personalizing or stratifying treatment regimes. In order to realize the potential of such approaches to predict new results, not merely to explain previous experimental findings, it is necessary that the methods used are reliable and accurate, and that their limitations are thoroughly understood. However, the computational cost of atomistic simulation techniques such as molecular dynamics (MD) has meant that until recently little work has focused on validating and verifying the available free energy methodologies, with the consequence that many of the results published in the literature are not reproducible. Here, we present a detailed analysis of two of the most popular approximate methods for calculating binding free energies from molecular simulations, molecular mechanics Poisson-Boltzmann surface area (MMPBSA) and molecular mechanics generalized Born surface area (MMGBSA), applied to the nine FDA-approved HIV-1 protease inhibitors. Our results show that the values obtained from replica simulations of the same protease-drug complex, differing only in initially assigned atom velocities, can vary by as much as 10 kcal mol-1, which is greater than the difference between the best and worst binding inhibitors under investigation. Despite this, analysis of ensembles of simulations producing 50 trajectories of 4 ns duration leads to well converged free energy estimates. For seven inhibitors, we find that with correctly converged normal mode estimates of the configurational entropy, we can correctly distinguish inhibitors in agreement with experimental data for both the MMPBSA and MMGBSA methods and thus have the ability to rank the efficacy of binding of this selection of drugs to the protease (no account is made for free energy penalties associated with protein distortion leading to the over estimation of the binding strength of the two largest inhibitors ritonavir and atazanavir). We obtain improved rankings and estimates of the relative binding strengths of the drugs by using a novel combination of MMPBSA/MMGBSA with normal mode entropy estimates and the free energy of association calculated directly from simulation trajectories. Our work provides a thorough assessment of what is required to produce converged and hence reliable free energies for protein-ligand binding.
RESUMO
Accurate calculation of important thermodynamic properties, such as macromolecular binding free energies, is one of the principal goals of molecular dynamics simulations. However, single long simulation frequently produces incorrectly converged quantitative results due to inadequate sampling of conformational space in a feasible wall-clock time. Multiple short (ensemble) simulations have been shown to explore conformational space more effectively than single long simulations, but the two methods have not yet been thermodynamically compared. Here we show that, for end-state binding free energy determination methods, ensemble simulations exhibit significantly enhanced thermodynamic sampling over single long simulations and result in accurate and converged relative binding free energies that are reproducible to within 0.5 kcal/mol. Completely correct ranking is obtained for six HIV-1 protease variants bound to lopinavir with a correlation coefficient of 0.89 and a mean relative deviation from experiment of 0.9 kcal/mol. Multidrug resistance to lopinavir is enthalpically driven and increases through a decrease in the protein-ligand van der Waals interaction, principally due to the V82A/I84V mutation, and an increase in net electrostatic repulsion due to water-mediated disruption of protein-ligand interactions in the catalytic region. Furthermore, we correctly rank, to within 1 kcal/mol of experiment, the substantially increased chemical potency of lopinavir binding to the wild-type protease compared to saquinavir and show that lopinavir takes advantage of a decreased net electrostatic repulsion to confer enhanced binding. Our approach is dependent on the combined use of petascale computing resources and on an automated simulation workflow to attain the required level of sampling and turn around time to obtain the results, which can be as little as three days. This level of performance promotes integration of such methodology with clinical decision support systems for the optimization of patient-specific therapy.
Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/enzimologia , Simulação de Dinâmica Molecular , Pirimidinonas/farmacologia , Fármacos Anti-HIV/química , Resistência a Múltiplos Medicamentos , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Protease de HIV/química , Inibidores da Protease de HIV/química , Humanos , Lopinavir , Pirimidinonas/química , TermodinâmicaRESUMO
We describe computational science research that uses petascale resources to achieve scientific results at unprecedented scales and resolution. The applications span a wide range of domains, from investigation of fundamental problems in turbulence through computational materials science research to biomedical applications at the forefront of HIV/AIDS research and cerebrovascular haemodynamics. This work was mainly performed on the US TeraGrid 'petascale' resource, Ranger, at Texas Advanced Computing Center, in the first half of 2008 when it was the largest computing system in the world available for open scientific research. We have sought to use this petascale supercomputer optimally across application domains and scales, exploiting the excellent parallel scaling performance found on up to at least 32 768 cores for certain of our codes in the so-called 'capability computing' category as well as high-throughput intermediate-scale jobs for ensemble simulations in the 32-512 core range. Furthermore, this activity provides evidence that conventional parallel programming with MPI should be successful at the petascale in the short to medium term. We also report on the parallel performance of some of our codes on up to 65 636 cores on the IBM Blue Gene/P system at the Argonne Leadership Computing Facility, which has recently been named the fastest supercomputer in the world for open science.