RESUMEN
The free energy perturbation (FEP) method is a powerful technique for accurate binding free energy calculations, which is crucial for identifying potent ligands with a high affinity in drug discovery. However, the widespread application of FEP is limited by the high computational cost required to achieve equilibrium sampling and the challenges in obtaining converged predictions. In this study, we present the convergence-adaptive roundtrip (CAR) method, which is an enhanced adaptive sampling approach, to address the key challenges in FEP calculations, including the precision-efficiency tradeoff, sampling efficiency, and convergence assessment. By employing on-the-fly convergence analysis to automatically adjust simulation times, enabling efficient traversal of the important phase space through rapid propagation of conformations between different states and eliminating the need for multiple parallel simulations, the CAR method increases convergence and minimizes computational overhead while maintaining calculation accuracy. The performance of the CAR method was evaluated through relative binding free energy (RBFE) calculations on benchmarks comprising four diverse protein-ligand systems. The results demonstrated a significant speedup of over 8-fold compared to conventional FEP methods while maintaining high accuracy. The overall R2 values of 0.65 and 0.56 were obtained using the combined-structure FEP approach and the single-step FEP approach, respectively, in conjunction with the CAR method. In-depth case studies further highlighted the superior performance of the CAR method in terms of convergence acceleration, improved predicted correlations, and reduced computational costs. The advancement of the CAR method makes it a highly effective approach, enhancing the applicability of FEP in drug discovery.
RESUMEN
The location of the grounding grid conductors is critical for performing corrosion diagnosis and maintenance work. An improved magnetic field differential method to locate the unknown grounding grid based on truncation errors and the round-off errors analysis is presented in this paper. It was proven that a different order of the magnetic field derivative can be used to determine the position of the grounding conductor according to the peak value of the derivative. Due to the accumulative error of higher differentiation, the truncation error and rounding error were used to analyze to accumulative error and to determine the optimal step size to measure and calculate the higher differentiation. The possible range and probability distribution of the two kinds of errors at each order are described, and the index of peak position error was derived, which can be used to locate the grounding conductor in the power substation.