AMOEBA+ Classical Potential for Modeling Molecular Interactions

Classical potentials based on isotropic and additive atomic charges have been widely used to model molecules in computers for the past few decades. The crude approximations in the underlying physics are hindering both their accuracy and transferability across chemical and physical environments. Here we present a new classical potential, AMOEBA+, to capture essential intermolecular forces, including permanent electrostatics, repulsion, dispersion, many-body polarization, short-range charge penetration, and charge transfer, by extending the polarizable multipole-based AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) model. For a set of common organic molecules, we show that AMOEBA+ with general parameters can reproduce both quantum mechanical interactions and energy decompositions according to Symmetry-Adapted Perturbation Theory (SAPT). Additionally, a new water model based on the AMOEBA+ framework captures various liquid-phase properties in molecular dynamics simulations while remaining consistent with SAPT energy decompositions, utilizing both ab initio data and experimental liquid properties. Our results demonstrate that it is possible to improve the physical basis of classical force fields to advance their accuracy and general applicability

Atomic Polarizabilities for Interactive Dipole Induction Models

Thole-style mutual induction models for molecular polarization have been adopted by several popular polarizable force fields (FFs) for their simplicity and transferability. The atomic polarizability parameters of these models are typically derived by fitting to ab initio or/and experimental molecular polarizabilities. In this work, we improve upon Thole polarizability parameters by employing both high-level quantum mechanics molecular polarizabilities and electrostatic potential (ESP) responses on three-dimensional grids. Our results indicate that the two approaches to derive atomic polarizability parameters are both effective, while the ESP approaches can also capture the polarization for the atoms with lone pair electrons. The resulting polarizability parameters have been validated on a set of over 7200 molecules covering the most common elements found in organic molecules (C, H, O, N, P, S, F, Cl, Br, and I). These parameters have also been tested on the experimentally measured molecular polarizabilities of 422 molecules. The final set of parameters derived in this work show notable improvement over the current AMOEBA set. The result is a highly transferable, expanded set of atomic polarizabilities defined by the local chemical environment in the form of SMARTS patterns. These parameters can be used directly in molecular mechanics polarizable potential energy functions such as AMOEBA, AMOEBA+, and other Thole-style models

AMOEBA+ Classical Potential for Modeling Molecular Interactions

Classical potentials based on isotropic and additive atomic charges have been widely used to model molecules in computers for the past few decades. The crude approximations in the underlying physics are hindering both their accuracy and transferability across chemical and physical environments. Here we present a new classical potential, AMOEBA+, to capture essential intermolecular forces, including permanent electrostatics, repulsion, dispersion, many-body polarization, short-range charge penetration, and charge transfer, by extending the polarizable multipole-based AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) model. For a set of common organic molecules, we show that AMOEBA+ with general parameters can reproduce both quantum mechanical interactions and energy decompositions according to Symmetry-Adapted Perturbation Theory (SAPT). Additionally, a new water model based on the AMOEBA+ framework captures various liquid-phase properties in molecular dynamics simulations while remaining consistent with SAPT energy decompositions, utilizing both ab initio data and experimental liquid properties. Our results demonstrate that it is possible to improve the physical basis of classical force fields to advance their accuracy and general applicability

AMOEBA+ Classical Potential for Modeling Molecular Interactions

Classical potentials based on isotropic and additive atomic charges have been widely used to model molecules in computers for the past few decades. The crude approximations in the underlying physics are hindering both their accuracy and transferability across chemical and physical environments. Here we present a new classical potential, AMOEBA+, to capture essential intermolecular forces, including permanent electrostatics, repulsion, dispersion, many-body polarization, short-range charge penetration, and charge transfer, by extending the polarizable multipole-based AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) model. For a set of common organic molecules, we show that AMOEBA+ with general parameters can reproduce both quantum mechanical interactions and energy decompositions according to Symmetry-Adapted Perturbation Theory (SAPT). Additionally, a new water model based on the AMOEBA+ framework captures various liquid-phase properties in molecular dynamics simulations while remaining consistent with SAPT energy decompositions, utilizing both ab initio data and experimental liquid properties. Our results demonstrate that it is possible to improve the physical basis of classical force fields to advance their accuracy and general applicability

Hyperandrogen enhances apoptosis of human ovarian granulosa cells via up-regulation and demethylation of PDCD4

Apoptosis of granulosa cells (GCs) induced by hyperandrogen plays a key role in the pathogenesis of polycystic ovary syndrome (PCOS). However, the mechanism of androgen-induced apoptosis of GCs has not been clarified to date. Recent studies have reported that PDCD4 expression is higher in PCOS patients and might be a key factor in PCOS progression. In this study, we aimed to investigate the role of PDCD4 in regulating apoptosis of human GCs and whether hyperandrogen regulate PDCD4 expression through DNA methylation. Overexpression of PDCD4 in human ovarian granulosa cell line KGN cells promoted cells apoptosis. Meanwhile, expression of caspase-3 and caspase-9 were significantly elevated. High concentration of testosterone treatment resulted in up-regulation of PDCD4 and a significant increase of apoptosis in KGN cells. In addition, knockdown of PDCD4 in KGN cells treated with high concentration of testosterone abolished the hyperandrogen-induced apoptosis. Furthermore, high concentration of testosterone down-regulated DNMT1, DNMT3A and DNMT3B expression and the methylation level in the promoter region of PDCD4 was decreased. In conclusion, PDCD4 can promote apoptosis of human ovarian GCs. The mechanism of hyperandrogen-induced apoptosis may be mediated by PDCD4. Furthermore, the up-regulation of PDCD4 induced by hyperandrogen may through demethylation of its promoter regions.</p

Incorporating Neural Networks into the AMOEBA Polarizable Force Field

Neural network potentials (NNPs) offer significant promise to bridge the gap between the accuracy of quantum mechanics and the efficiency of molecular mechanics in molecular simulation. Most NNPs rely on the locality assumption that ensures the model’s transferability and scalability and thus lack the treatment of long-range interactions, which are essential for molecular systems in the condensed phase. Here we present an integrated hybrid model, AMOEBA+NN, which combines the AMOEBA potential for the short- and long-range noncovalent atomic interactions and an NNP to capture the remaining local covalent contributions. The AMOEBA+NN model was trained on the conformational energy of the ANI-1x data set and tested on several external data sets ranging from small molecules to tetrapeptides. The hybrid model demonstrated substantial improvements over the baseline models in term of accuracy as the molecule size increased, suggesting its potential as a next-generation approach for chemically accurate molecular simulations

Elucidating the Phosphate Binding Mode of Phosphate-Binding Protein: The Critical Effect of Buffer Solution

Phosphate is an essential component of cell functions, and the specific transport of phosphorus into a cell is mediated by phosphate-binding protein (PBP). The mechanism of PBP-phosphate recognition remains controversial: on the basis of similar binding affinities at acidic and basic pHs, it is believed that the hydrogen network in the binding site is flexible to adapt to different protonation states of phosphates. However, only hydrogen (1H) phosphate was observed in the sub-angstrom X-ray structures. To address this inconsistency, we performed molecular dynamics simulations using the AMOEBA polarizable force field. Structural and free energy data from simulations suggested that 1H phosphate was the preferred bound form at both pHs. The binding of dihydrogen (2H) phosphate disrupted the hydrogen-bond network in the PBP pocket, and the computed affinity was much weaker than that of 1H phosphate. Furthermore, we showed that the discrepancy in the studies described above is resolved if the interaction between phosphate and the buffer agent is taken into account. The calculated apparent binding affinities are in excellent agreement with experimental measurements. Our results suggest the high specificity of PBP for 1H phosphate and highlight the importance of the buffer solution for the binding of highly charged ligands

Development of AMOEBA Polarizable Force Field for Rare-Earth La³⁺ Interaction with Bioinspired Ligands

Rare-earth metals (REMs) are crucial for many important industries, such as power generation and storage, in addition to cancer treatment and medical imaging. One promising new REM refinement approach involves mimicking the highly selective and efficient binding of REMs observed in relatively recently discovered proteins. However, realizing any such bioinspired approach requires an understanding of the biological recognition mechanisms. Here, we developed a new classical polarizable force field based on the AMOEBA framework for modeling a lanthanum ion (La3+) interacting with water, acetate, and acetamide, which have been found to coordinate the ion in proteins. The parameters were derived by comparing to high-level ab initio quantum mechanical (QM) calculations that include relativistic effects. The AMOEBA model, with advanced atomic multipoles and electronic polarization, is successful in capturing both the QM distance-dependent La3+–ligand interaction energies and experimental hydration free energy. A new scheme for pairwise polarization damping (POLPAIR) was developed to describe the polarization energy in La3+ interactions with both charged and neutral ligands. Simulations of La3+ in water showed water coordination numbers and ion–water distances consistent with previous experimental and theoretical findings. Water residence time analysis revealed both fast and slow kinetics in water exchange around the ion. This new model will allow investigation of fully solvated lanthanum ion–protein systems using GPU-accelerated dynamics simulations to gain insights on binding selectivity, which may be applied to the design of synthetic analogues

Development of AMOEBA Polarizable Force Field for Rare-Earth La³⁺ Interaction with Bioinspired Ligands

Rare-earth metals (REMs) are crucial for many important industries, such as power generation and storage, in addition to cancer treatment and medical imaging. One promising new REM refinement approach involves mimicking the highly selective and efficient binding of REMs observed in relatively recently discovered proteins. However, realizing any such bioinspired approach requires an understanding of the biological recognition mechanisms. Here, we developed a new classical polarizable force field based on the AMOEBA framework for modeling a lanthanum ion (La3+) interacting with water, acetate, and acetamide, which have been found to coordinate the ion in proteins. The parameters were derived by comparing to high-level ab initio quantum mechanical (QM) calculations that include relativistic effects. The AMOEBA model, with advanced atomic multipoles and electronic polarization, is successful in capturing both the QM distance-dependent La3+–ligand interaction energies and experimental hydration free energy. A new scheme for pairwise polarization damping (POLPAIR) was developed to describe the polarization energy in La3+ interactions with both charged and neutral ligands. Simulations of La3+ in water showed water coordination numbers and ion–water distances consistent with previous experimental and theoretical findings. Water residence time analysis revealed both fast and slow kinetics in water exchange around the ion. This new model will allow investigation of fully solvated lanthanum ion–protein systems using GPU-accelerated dynamics simulations to gain insights on binding selectivity, which may be applied to the design of synthetic analogues