Mazzaferro, N. | Search bioRxiv

bioRxiv2025

Using Time Dependent Rate Analysis to Evaluate the Quality of Machine Learned Reaction Coordinates for Biasing and Computing Kinetics

Having an accurate reaction coordinate (RC) is essential for reliable kinetic characterization of molecular processes, but there are few quantitative metrics to evaluate RC quality. In this study, we consider the dimensionless{gamma} metric from the Exponential Average Time-dependent Rate (EATR) method, which represents the fraction of a biasing potential along the RC that contributes to increasing the rate constant. We demonstrate that{gamma} can be used to test whether the utility of a reaction coordinate for predicting kinetics with a Meta-dynamics bias improves as the coordinate is iteratively updated to include new data. We evaluate reaction coordinates approximated via the iterative State Predictive Information Bottleneck (SPIB) approach, which was previously shown to be accurate across six protein-ligand dissociation systems. For these same systems, we compute{gamma} values and mean accelerated times [Formula]. After systematically scanning over fitting parameters, the results show that{gamma} increases closer to 1, while [Formula] decreases, revealing a consistent inverse correlation. These results demonstrate that{gamma} serves as a practical criterion for RC evaluation and offers guidance for selecting SPIB-derived coordinates yielding quantitative kinetic predictions.

biophysics↗

bioRxiv2024

Flanking Domains Modulate α-Synuclein Monomer Structure: A Molecular Dynamics Domain Deletion Study

Aggregates of misfolded -synuclein proteins (asyn) are key markers of Parkinsons disease. Asyn proteins have three domains: an N-terminal domain, a hydrophobic NAC core implicated in aggregation, and a proline-rich C-terminal domain. Proteins with truncated C-terminal domains are known to be prone to aggregation and suggest that understanding domain-domain interactions in asyn monomers could help elucidate the role of the flanking domains in modulating protein structure. To this end, we used Gaussian accelerated molecular dynamics (GAMD) to simulate wild-type (WT), N-terminal truncated ({Delta}N), C-terminal truncated ({Delta}C), and isolated NAC domain asyn protein variants (isoNAC). Using clustering and contact analysis, we found that removal of the N-terminal domain led to increased contacts between NAC and C-terminal domains and the formation of interdomain {Delta}-sheets. Removal of either flanking domain also resulted in increased compactness of every domain. We also found that the contacts between flanking domains in the WT protein result in an electrostatic potential (ESP) that may lead to favorable interactions with anionic lipid membranes. Removal of the C-terminal domain disrupts the ESP in a way that could result in over-stabilized protein-membrane interactions. These results suggests that cooperation between the flanking domains may modulate the proteins structure in a way that helps maintain elongation and creates an ESP that may aid favorable interactions with the membrane.

biophysics↗