A green solvent screening tool for emerging materials via uncertainty aware, transformer enhanced transfer learning
Authors: Ioannis Kouroudis, Simon Ternes, Zhaosu Gu, Gohar Ali Siddiqui, Marina Ustinova, Angelo Lembo, Alessio Gagliardi, Aldo Di Carlo
Abstract
Accurate prediction of solubility remains a central challenge across materials science and sustainable chemistry. In particular due to emerging technologies like organic and hybrid photovoltaics, batteries, and catalysis, solvent usage is expected to increase significantly within the coming years. Therefore, substituting solvents with greener alternatives is vital. This is where machine learning can have substantial impact. However, the limited data on critical parameters of solubility significantly constraints machine learning efficacy. In this work, we transfer a pre-trained foundational model on QM9 targets to our application with minimal data requirements. Additionally, the pipeline integrates uncertainty quantification, allowing the user to gauge the confidence of the predictions. As baseline, we succeed in predicting the Hansen solubility parameters and Dielectric Constant for which extensive databases exist. Importantly, we achieve high model performance on additional targets, such as Gutmann Donor and Acceptor numbers, where the available data is extremely limited. Overall, we augment data on solubility descriptors by orders of magnitude with high quality predictions. For effective dissemination, we deploy easy-to-use, easily integrateable with high throughput labs, customizable tool for ranking and screening possible solvent substitutes. Finally, we rediscovered known green solvent alternatives and proposed new candidates proving its relevance for finding eco-friendly solvents.
Implicit solvent machine learning potentials (MLPs) offer a powerful route to bridging the gap between accuracy and efficiency in molecular simulations. However, existing models have largely focused on aqueous environments, overlooking the diverse and important roles of non-aqueous solvents in areas such as organic synthesis and battery technology. Here, we present ConSolv, a solvent-conditional MLP architecture that explicitly incorporates solvent effects on solute interactions through an attention-based solvent-embedding block. By combining experimental solvation free energy data with ab initio data, we train a single implicit solvent MLP that is transferable across 66 common organic solvents. ConSolv outperforms classical explicit solvent methods and selected ab initio implicit solvent approaches across multiple solvation free energy benchmarks, and demonstrates generalization to unseen solvents. Beyond solvation free energies, the model shows close agreement with experimental nuclear magnetic resonance (NMR) data for γ-fluorohydrin molecules in chloroform. ConSolv's architecture is readily extensible to broader chemical spaces and alternative training strategies, while its attention-based design supports explainable artificial intelligence (AI) analysis that can help elucidate complex, solvent-dependent molecular interactions.
Solubility prediction is a standard benchmark in computational chemistry, yet multi-solvent models which reportedly approach the experimental-noise ceiling (i.e. the aleatoric limit) are not yet reliable enough to be deployed. We argue that this gap is partly artefactual: published benchmarks differ in curation policies, evaluate on count-weighted RMSE that hides failure on tail-heavy solvent distributions, and treat the widely cited 0.6-0.8 log S inter-laboratory figure as the aleatoric ceiling even though it reflects worst-case, not expected, disagreement. We introduce SC3, a multi-solvent solubility benchmark built on BigSolDB v2.1 with three contributions: (i) a reproducible curation pipeline yielding 101,535 measurements over 1,327 solutes and 206 solvents, with a recalibrated aleatoric floor of 0.106 log S-roughly 6 times tighter than the conventional figure; (ii) nested Gold/Silver/Bronze consensus tiers with per-point standard deviation, three leakage-checked splits, and a multi-solvent metric suite (PS-RMSE, Z-RMSE); and (iii) a 31-model benchmark across six families, whose best Bronze PS-RMSE sits at 5 times the aleatoric limit, and we observe this is a gap unclosed by any deep alternative tested. We perform three follow-on analyses: data scaling, transfer from quantum-chemistry solvation energies, and feature-level attribution, which demonstrates that calibrated per-point uncertainty is a reusable infrastructure for diagnosis beyond point prediction.
Vansh Ramani, Har Ashish Arora, Dhairya Kuchhal +4
Implicit solvent models are widely used to decrease the number of solvent degrees of freedom and enable the calculation of solvation energetics without water molecules. However, its accuracy often falls short compared to explicit models. Recent advancements in neural potentials have shown promise in drug discovery, but transferability remains a persistent challenge. Here, we introduce the Protein Hydration Neural Network (PHNN), an implicit solvent model that extends analytical continuum solvation by learning transferable corrections to model parameters instead of applying post hoc adjustments to final energies. The model is explicitly designed to maximize data efficiency by leveraging physical priors embedded in the data. We demonstrate that PHNN improves accuracy relative to traditional analytical methods and maintains predictive accuracy on out-of-domain protein systems.