Generating High-Precision Force Fields for Molecular Dynamics Simulations to Study Chemical Reaction Mechanisms using Molecular Configuration Transformer

Theoretical studies on chemical reaction mechanisms have been crucial in organic chemistry. Traditionally, calculating the manually constructed molecular conformations of transition states for chemical reactions using quantum chemical calculations is the most commonly used method. However, this way is heavily dependent on individual experience and chemical intuition. In our previous study, we proposed a research paradigm that uses enhanced sampling in QM/MM molecular dynamics simulations to study chemical reactions. This approach can directly simulate the entire process of a chemical reaction. However, the computational speed limits the use of high-precision potential energy functions for simulations. To address this issue, we present a scheme for training high-precision force fields for molecular modeling using our developed graph-neural-network-based molecular model, molecular configuration transformer. This potential energy function allows for highly accurate simulations at a low computational cost, leading to more precise calculations of the mechanism of chemical reactions. We have used this approach to study a Cope rearrangement reaction and a Carbonyl insertion reaction catalyzed by Manganese. This "AI+Physics" based simulation approach is expected to become a new trend in the theoretical study of organic chemical reaction mechanisms.

Machine-Learned Invertible Coarse Graining for Multiscale Molecular Modeling

Multiscale molecular modeling is widely applied in scientific research of molecular properties over large time and length scales. Two specific challenges are commonly present in multiscale modeling, provided that information between the coarse and fine representations of molecules needs to be properly exchanged: One is to construct coarse grained (CG) models by passing information from the fine to coarse levels; the other is to restore finer molecular details given CG configurations. Although these two problems are commonly addressed independently, in this work, we present a theory connecting them, and develop a methodology called Cycle Coarse Graining (CCG) to solve both problems in a unified manner. In CCG, reconstruction can be achieved via a tractable optimization process, leading to a general method to retrieve fine details from CG simulations, which in turn, delivers a new solution to the CG problem, yielding an efficient way to calculate free energies in a rare-event-free manner. CCG thus provides a systematic way for multiscale molecular modeling, where the finer details of CG simulations can be efficiently retrieved, and the CG models can be improved consistently.

DSDP: A Blind Docking Strategy Accelerated by GPUs

Virtual screening, including molecular docking, plays an essential role in drug discovery. Many traditional and machine-learning based methods are available to fulfil the docking task. The traditional docking methods are normally extensively time-consuming, and their performance in blind docking remains to be improved. Although the runtime of docking based on machine learning is significantly decreased, their accuracy is still limited. In this study, we take the advantage of both traditional and machine-learning based methods, and present a method Deep Site and Docking Pose (DSDP) to improve the performance of blind docking. For the traditional blind docking, the entire protein is covered by a cube, and the initial positions of ligands are randomly generated in the cube. In contract, DSDP can predict the binding site of proteins and provide an accurate searching space and initial positions for the further conformational sampling. The docking task of DSDP makes use of the score function and a similar but modified searching strategy of AutoDock Vina, accelerated by implementation in GPUs. We systematically compare its performance with the state-of-the-art methods, including Autodock Vina, GNINA, QuickVina, SMINA, and DiffDock. DSDP reaches a 29.8% top-1 success rate (RMSD < 2 {\AA}) on an unbiased and challenging test dataset with 1.2 s wall-clock computational time per system. Its performances on DUD-E dataset and the time-split PDBBind dataset used in EquiBind, TankBind, and DiffDock are also effective, presenting a 57.2% and 41.8% top-1 success rate with 0.8 s and 1.0 s per system, respectively.

Few-Shot Learning of Accurate Folding Landscape for Protein Structure Prediction

Data-driven predictive methods which can efficiently and accurately transform protein sequences into biologically active structures are highly valuable for scientific research and therapeutical development. Determining accurate folding landscape using co-evolutionary information is fundamental to the success of modern protein structure prediction methods. As the state of the art, AlphaFold2 has dramatically raised the accuracy without performing explicit co-evolutionary analysis. Nevertheless, its performance still shows strong dependence on available sequence homologs. We investigated the cause of such dependence and presented EvoGen, a meta generative model, to remedy the underperformance of AlphaFold2 for poor MSA targets. EvoGen allows us to manipulate the folding landscape either by denoising the searched MSA or by generating virtual MSA, and helps AlphaFold2 fold accurately in low-data regime or even achieve encouraging performance with single-sequence predictions. Being able to make accurate predictions with few-shot MSA not only generalizes AlphaFold2 better for orphan sequences, but also democratizes its use for high-throughput applications. Besides, EvoGen combined with AlphaFold2 yields a probabilistic structure generation method which could explore alternative conformations of protein sequences, and the task-aware differentiable algorithm for sequence generation will benefit other related tasks including protein design.

PSP: Million-level Protein Sequence Dataset for Protein Structure Prediction

Proteins are essential component of human life and their structures are important for function and mechanism analysis. Recent work has shown the potential of AI-driven methods for protein structure prediction. However, the development of new models is restricted by the lack of dataset and benchmark training procedure. To the best of our knowledge, the existing open source datasets are far less to satisfy the needs of modern protein sequence-structure related research. To solve this problem, we present the first million-level protein structure prediction dataset with high coverage and diversity, named as PSP. This dataset consists of 570k true structure sequences (10TB) and 745k complementary distillation sequences (15TB). We provide in addition the benchmark training procedure for SOTA protein structure prediction model on this dataset. We validate the utility of this dataset for training by participating CAMEO contest in which our model won the first place. We hope our PSP dataset together with the training benchmark can enable a broader community of AI/biology researchers for AI-driven protein related research.

Molecular CT: Unifying Geometry and Representation Learning for Molecules at Different Scales

Deep learning is changing many areas in molecular physics, and it has shown great potential to deliver new solutions to challenging molecular modeling problems. Along with this trend arises the increasing demand of expressive and versatile neural network architectures which are compatible with molecular systems. A new deep neural network architecture, Molecular Configuration Transformer (Molecular CT), is introduced for this purpose. Molecular CT is composed of a relation-aware encoder module and a computationally universal geometry learning unit, thus able to account for the relational constraints between particles meanwhile scalable to different particle numbers and invariant w.r.t. the trans-rotational transforms. The computational efficiency and universality make Molecular CT versatile for a variety of molecular learning scenarios and especially appealing for transferable representation learning across different molecular systems. As examples, we show that Molecular CT enables representational learning for molecular systems at different scales, and achieves comparable or improved results on common benchmarks using a more light-weighted structure compared to baseline models.

Deep Reinforcement Learning of Transition States

Combining reinforcement learning (RL) and molecular dynamics (MD) simulations, we propose a machine-learning approach (RL$^\ddag$) to automatically unravel chemical reaction mechanisms. In RL$^\ddag$, locating the transition state of a chemical reaction is formulated as a game, where a virtual player is trained to shoot simulation trajectories connecting the reactant and product. The player utilizes two functions, one for value estimation and the other for policy making, to iteratively improve the chance of winning this game. We can directly interpret the reaction mechanism according to the value function. Meanwhile, the policy function enables efficient sampling of the transition paths, which can be further used to analyze the reaction dynamics and kinetics. Through multiple experiments, we show that RL{\ddag} can be trained tabula rasa hence allows us to reveal chemical reaction mechanisms with minimal subjective biases.

A Perspective on Deep Learning for Molecular Modeling and Simulations

Deep learning is transforming many areas in science, and it has great potential in modeling molecular systems. However, unlike the mature deployment of deep learning in computer vision and natural language processing, its development in molecular modeling and simulations is still at an early stage, largely because the inductive biases of molecules are completely different from those of images or texts. Footed on these differences, we first reviewed the limitations of traditional deep learning models from the perspective of molecular physics, and wrapped up some relevant technical advancement at the interface between molecular modeling and deep learning. We do not focus merely on the ever more complex neural network models, instead, we emphasize the theories and ideas behind modern deep learning. We hope that transacting these ideas into molecular modeling will create new opportunities. For this purpose, we summarized several representative applications, ranging from supervised to unsupervised and reinforcement learning, and discussed their connections with the emerging trends in deep learning. Finally, we outlook promising directions which may help address the existing issues in the current framework of deep molecular modeling.

Learning Clustered Representation for Complex Free Energy Landscapes

In this paper we first analyzed the inductive bias underlying the data scattered across complex free energy landscapes (FEL), and exploited it to train deep neural networks which yield reduced and clustered representation for the FEL. Our parametric method, called Information Distilling of Metastability (IDM), is end-to-end differentiable thus scalable to ultra-large dataset. IDM is also a clustering algorithm and is able to cluster the samples in the meantime of reducing the dimensions. Besides, as an unsupervised learning method, IDM differs from many existing dimensionality reduction and clustering methods in that it neither requires a cherry-picked distance metric nor the ground-true number of clusters, and that it can be used to unroll and zoom-in the hierarchical FEL with respect to different timescales. Through multiple experiments, we show that IDM can achieve physically meaningful representations which partition the FEL into well-defined metastable states hence are amenable for downstream tasks such as mechanism analysis and kinetic modeling.