LigandDiff: de Novo Ligand Design for 3D Transition Metal Complexes with Diffusion Models.

Transition metal complexes are a class of compounds with varied and versatile properties, making them of great technological importance. Their applications cover a wide range of fields, either as metallodrugs in medicine or as materials, catalysts, batteries, solar cells, etc. The demand for the novel design of transition metal complexes with new properties remains of great interest. However, the traditional high-throughput screening approach is inherently expensive and laborious since it depends on human expertise. Here, we present LigandDiff, a generative model for the de novo design of novel transition metal complexes. Unlike the existing methods that simply extract and combine ligands with the metal to get new complexes, LigandDiff aims at designing configurationally novel ligands from scratch, which opens new pathways for the discovery of organometallic complexes. Moreover, it overcomes the limitations of current methods, where the diversity of new complexes highly relies on the diversity of available ligands, while LigandDiff can design numerous novel ligands without human intervention. Our results indicate that LigandDiff designs unique and novel ligands under different contexts, and these generated ligands are synthetically accessible. Moreover, LigandDiff shows good transferability by generating successful ligands for any transition metal complex.

Modeling Zinc Complexes Using Neural Networks.

Understanding the energetic landscapes of large molecules is necessary for the study of chemical and biological systems. Recently, deep learning has greatly accelerated the development of models based on quantum chemistry, making it possible to build potential energy surfaces and explore chemical space. However, most of this work has focused on organic molecules due to the simplicity of their electronic structures as well as the availability of data sets. In this work, we build a deep learning architecture to model the energetics of zinc organometallic complexes. To achieve this, we have compiled a configurationally and conformationally diverse data set of zinc complexes using metadynamics to overcome the limitations of traditional sampling methods. In terms of the neural network potentials, our results indicate that for zinc complexes, partial charges play an important role in modeling the long-range interactions with a neural network. Our developed model outperforms semiempirical methods in predicting the relative energy of zinc conformers, yielding a mean absolute error (MAE) of 1.32 kcal/mol with reference to the double-hybrid PWPB95 method.

Modeling Fe(II) Complexes Using Neural Networks.

We report a Fe(II) data set of more than 23000 conformers in both low-spin (LS) and high-spin (HS) states. This data set was generated to develop a neural network model that is capable of predicting the energy and the energy splitting as a function of the conformation of a Fe(II) organometallic complex. In order to achieve this, we propose a type of scaled electronic embedding to cover the long-range interactions implicitly in our neural network describing the Fe(II) organometallic complexes. For the total energy prediction, the lowest MAE is 0.037 eV, while the lowest MAE of the splitting energy is 0.030 eV. Compared to baseline models, which only incorporate short-range interactions, our scaled electronic embeddings improve the accuracy by over 70% for the prediction of the total energy and the splitting energy. With regard to semiempirical methods, our proposed models reduce the MAE, with respect to these methods, by 2 orders of magnitude.