Coarse graining enables the investigation of molecular dynamics for larger systems and at longer timescales than is possible at an atomic resolution. However, a coarse graining model must be formulated such that the conclusions we draw from it are consistent with the conclusions we would draw from a model at a finer level of detail. It has been proved that a force matching scheme defines a thermodynamically consistent coarse-grained model for an atomistic system in the variational limit. Wang et al. [ACS Cent. Sci. 5, 755 (2019)] demonstrated that the existence of such a variational limit enables the use of a supervised machine learning framework to generate a coarse-grained force field, which can then be used for simulation in the coarse-grained space. Their framework, however, requires the manual input of molecular features to machine learn the force field. In the present contribution, we build upon the advance of Wang et al. and introduce a hybrid architecture for the machine learning of coarse-grained force fields that learn their own features via a subnetwork that leverages continuous filter convolutions on a graph neural network architecture. We demonstrate that this framework succeeds at reproducing the thermodynamics for small biomolecular systems. Since the learned molecular representations are inherently transferable, the architecture presented here sets the stage for the development of machine-learned, coarse-grained force fields that are transferable across molecular systems.

The use of coarse-grained (CG) models is a popular approach to study complex biomolecular systems. By reducing the number of degrees of freedom, a CG model can explore long time- and length-scales inaccessible to computational models at higher resolution. If a CG model is designed by formally integrating out some of the system’s degrees of freedom, one expects multi-body interactions to emerge in the effective CG model’s energy function. In practice, it has been shown that the inclusion of multi-body terms indeed improves the accuracy of a CG model. However, no general approach has been proposed to systematically construct a CG effective energy that includes arbitrary orders of multi-body terms. In this work, we propose a neural network based approach to address this point and construct a CG model as a multi-body expansion. By applying this approach to a small protein, we evaluate the relative importance of the different multi-body terms in the definition of an accurate model. We observe a slow convergence in the multi-body expansion, where up to five-body interactions are needed to reproduce the free energy of an atomistic model.

Gradient-domain machine learning (GDML) is an accurate and efficient approach to learn a molecular potential and associated force field based on the kernel ridge regression algorithm. Here, we demonstrate its application to learn an effective coarse-grained (CG) model from all-atom simulation data in a sample efficient manner. The CG force field is learned by following the thermodynamic consistency principle, here by minimizing the error between the predicted CG force and the all-atom mean force in the CG coordinates. Solving this problem by GDML directly is impossible because coarse-graining requires averaging over many training data points, resulting in impractical memory requirements for storing the kernel matrices. In this work, we propose a data-efficient and memory-saving alternative. Using ensemble learning and stratified sampling, we propose a 2-layer training scheme that enables GDML to learn an effective CG model. We illustrate our method on a simple biomolecular system, alanine dipeptide, by reconstructing the free energy landscape of a CG variant of this molecule. Our novel GDML training scheme yields a smaller free energy error than neural networks when the training set is small, and a comparably high accuracy when the training set is sufficiently large.