Molecular surfaces play a pivotal role in elucidating the properties and functions of biological complexes. While various surfaces have been proposed for specific scenarios, their widespread adoption faces challenges due to limited efficiency stemming from hand-crafted modeling designs. In this work, we proposed a general framework that incorporates both the point cloud concept and neural networks. The use of matrix multiplication in this framework enables efficient implementation across diverse platforms and libraries. We applied this framework to develop the GENIUSES (Grid-robust Efficient Neural Interface for Universal Solvent-Excluded Surface) model for constructing SES. GENIUSES demonstrates high accuracy and efficiency across data sets with varying conformations and complexities. Compared to the classical implementation of SES in the AMBER software package, our framework achieved a 26-fold speedup while retaining ∼95% accuracy when ported to the GPU platform using CUDA. Greater speedups can be obtained in large-scale systems. Importantly, our model exhibits robustness against variations in the grid spacing. We have integrated this infrastructure into AMBER to enhance accessibility for research in drug screening and related fields, where efficiency is of paramount importance.

Accurate characterization of electrostatic interactions is crucial in molecular simulation. Various methods and programs have been developed to obtain electrostatic parameters for additive or polarizable models to replicate electrostatic properties obtained from experimental measurements or theoretical calculations. Electrostatic potentials (ESPs), a set of physically well-defined observables from quantum mechanical (QM) calculations, are well suited for the optimization efforts due to the ease to collect large amount of conformation-dependent data. However, a reliable set of QM ESP computed at an appropriate level of theory and atomic basis set is necessary. In addition, despite the recent development of the PyRESP program for electrostatic 1 parameterizations of induced dipole polarizable models, the time-consuming and error-prone input file preparation process has limited the widespread use of these protocols. This work aims to comprehensively evaluate the quality of QM ESPs derived by eight methods, including wave function methods such as Hartree-Fock, second-order Møller-Pleeset (MP2), and coupled cluster-singles and doubles (CCSD), as well as five hybrid density functional theory (DFT) methods, used in conjunction with 13 different basis sets. The highest theory levels CCSD/aug-cc-pV5Z (a5z) and MP2/aug-cc-pV5Z (a5z) were selected as benchmark data over two homemade datasets. The results show that the hybrid DFT method, ωB97X-D, combined with the aug-cc-pVTZ (a3z) basis set, performs well in reproducing ESPs while taking both accuracy and efficiency into consideration. Moreover, a flexible and user-friendly program called PyRESP_GEN was developed to minimize human efforts required in input file preparation. The restraining strengths, along with strategies for polarizable Gaussian multipole (pGM) model parameterizations, were also optimized. These findings and the program presented in this work facilitate the development and application of induced dipole polarizable models such as pGM models for molecular simulations of both chemical and biological significance.

Target deconvolution is a crucial but costly and time-consuming task that hinders large-scale profiling for drug discovery. We present a matrix-augmented pooling strategy (MAPS) which mixes multiple drugs into samples with optimized permutation and delineates targets of each drug simultaneously with mathematical processing. We validated this strategy with thermal proteome profiling (TPP) testing of 15 drugs concurrently, increasing experimental throughput by 60x while maintaining high sensitivity and specificity. Benefiting from the lower cost and higher throughput of MAPS, we performed target deconvolution of the 15 drugs across 5 cell lines. Our profiling revealed that drug-target interactions can differ vastly in targets and binding affinity across cell lines. We further validated BRAF and CSNK2A2 as potential off-targets of bafetinib and abemaciclib, respectively. This work represents the largest thermal profiling of structurally diverse drugs across multiple cell lines to date.

Induced dipole models have proven to be effective tools for simulating electronic polarization effects in biochemical processes, yet their potential has been constrained by energy conservation issue, particularly when historical data is utilized for dipole prediction. This study identifies error outliers as the primary factor causing this failure of energy conservation and proposes a comprehensive scheme to overcome this limitation. Leveraging maximum relative errors as a convergence metric, our data demonstrates that energy conservation can be upheld even when using historical information for dipole predictions. Our study introduces the multi-order extrapolation method to quicken induction iteration and optimize the use of historical data, while also developing the preconditioned conjugate gradient with local iterations to refine the iteration process and effectively remove error outliers. This scheme further incorporates a "peek" step via Jacobi under-relaxation for optimal performance. Simulation evidence suggests that our proposed scheme can achieve energy convergence akin to that of point-charge models within a limited number of iterations, thus promising significant improvements in efficiency and accuracy.