Journal Article

Blind prediction of complex water and ion ensembles around RNA in CASP16

Sato, Kengo, Kihara, Daisuke, Krishnan, Sowmya Ramaswamy, Chiu, Wah, Hu, Gang, Ni, Wentao, Cheatham, 3rd, Thomas E, Nakamura, Tsukasa, Languin-Cattoën, Olivier, Nithin, Chandran, Case, David A, Chen, Shi-Jie, Pilla, Smita P, Bujnicki, Janusz M, Harini, K, Poblete, Simón, Bussi, Giovanni, Iwakiri, Junichi, Tugolukova, Emilia, Kagaya, Yuki, Terashi, Genki, Saha, Anouka, Kurisaki, Ikuo, Posani, Elisa, Das, Rhiju, Wuyun, Qiqige, Hamada, Michiaki, Zhang, Sicheng, Jain, Anika, Zheng, Wei, Farsani, Masoud Amiri, Gromiha, M Michael, Huang, David, Zerze, Gül H, Fisher, Olivia N, Zhou, Yuanzhe, Punuru, Pranav, Malekzadeh, Karim, Palo, Michael Z, Kmiecik, Sebastian, Verburgt, Jacob, Elofsson, Arne, Li, Jun, Pucci, Fabrizio, Kretsch, Rachael C, Gupta, Ayush, Park, Joon Hong, Zhang, Kaiming, Baulin, Eugene F, Srivastava, Ambuj, Li, Shanshan

2025

Overview

Biomolecules rely on water and ions for stable folding, but these interactions are often transient, dynamic, or disordered and thus hidden from experiments and evaluation challenges that represent biomolecules as single, ordered structures. Here, we compare blindly predicted ensembles of water and ion structure to the cryo-EM densities observed around the ribozyme at 2.2-2.3 Å resolution, collected through target R1260 in the CASP16 competition. 26 groups participated in this solvation 'cryo-ensemble' prediction challenge, submitting over 350 million atoms in total, offering the first opportunity to compare blind predictions of dynamic solvent shell ensembles to cryo-EM density. Predicted atomic ensembles were converted to density through local alignment and these densities were compared to the cryo-EM densities using Pearson correlation, Spearman correlation, mutual information, and precision-recall curves. These predictions show that an ensemble representation is able to capture information of transient or dynamic water and ions better than traditional atomic models, but there remains a large accuracy gap to the performance ceiling set by experimental uncertainty. Overall, molecular dynamics approaches best matched the cryo-EM density, with blind predictions from bussilab_plain_md, SoutheRNA, bussilab_replex, coogs2, and coogs3 outperforming the baseline molecular dynamics prediction. This study indicates that simulations of water and ions can be quantitatively evaluated with cryo-EM maps. We propose that further community-wide blind challenges can drive and evaluate progress in modeling water, ions and other previously hidden components of biomolecular systems.

• Publisher: Cold Spring Harbor Laboratory,Cold Spring Harbor Laboratory Preprints
• Subject: Biophysics