Biology subjects

Irvin, M.

Publications and source records attributed to Irvin, M..

3 recordsLinked to original sources

bioRxiv2026

Folding-Driven Control of the Functional PP1 Complex via Multiscale Modeling

Understanding how conformational dynamics regulate protein complex assembly remains a central challenge in molecular systems biology. Here, we develop a multiscale modeling framework that integrates all-atom molecular dynamics (MD) simulations with rule-based kinetic modeling to investigate the formation of the PP1-GADD34-eIF2 complex, a critical regulator of the integrated stress response. Using umbrella sampling, we compute the potential of mean force (PMF) for key interactions, revealing strong thermodynamic driving forces for eIF2 binding ({Delta}G = -89.5 kJ/mol, KD {approx} 0.07 fM) and moderate affinity for PP1-GADD34 association ({Delta}G = -40.7 kJ/mol, KD {approx} 0.138 M). These energetics inform a PySB-based model that incorporates GADD34's folding state as a continuous variable ({varphi}), linking conformational transitions to holoenzyme assembly and activity. Simulations show that catalytic efficiency is maximized when GADD34 folding free energy is 20 kJ/mol and {varphi} = 0.9, reflecting a highly ordered state stabilized by actin and PP1 binding. Comparative analysis of energy-constrained and optimized parameter regimes reveals that folding-dependent assembly enhances both eIF2 dephosphorylation and information transmission, with channel capacities increasing from <0.002 bits to >5.5 bits. These results demonstrate how conformational regulation encodes system-level function and underscore the utility of multiscale models in bridging molecular energetics with dynamic biochemical control.

biophysics↗

bioRxiv2022

GenSLMs: Genome-scale language models reveal SARS-CoV-2 evolutionary dynamics.

We seek to transform how new and emergent variants of pandemiccausing viruses, specifically SARS-CoV-2, are identified and classified. By adapting large language models (LLMs) for genomic data, we build genome-scale language models (GenSLMs) which can learn the evolutionary landscape of SARS-CoV-2 genomes. By pretraining on over 110 million prokaryotic gene sequences and finetuning a SARS-CoV-2-specific model on 1.5 million genomes, we show that GenSLMs can accurately and rapidly identify variants of concern. Thus, to our knowledge, GenSLMs represents one of the first whole genome scale foundation models which can generalize to other prediction tasks. We demonstrate scaling of GenSLMs on GPU-based supercomputers and AI-hardware accelerators utilizing 1.63 Zettaflops in training runs with a sustained performance of 121 PFLOPS in mixed precision and peak of 850 PFLOPS. We present initial scientific insights from examining GenSLMs in tracking evolutionary dynamics of SARS-CoV-2, paving the path to realizing this on large biological data.

bioinformatics↗

bioRxiv2021

The misleading certainty of uncertain data in biological network processes

Mathematical models are often used to explore network-driven cellular processes from a systems perspective. However, a dearth of quantitative data suitable for model calibration leads to models with parameter unidentifiability and questionable predictive power. Here we introduce a Bayesian and Machine-Learning based Measurement Model approach to explore how quantitative and non-quantitative data constrain models of apoptosis execution within a missing data context. We find two orders of magnitude more ordinal (e.g. immunoblot) data are necessary to achieve accuracy comparable to quantitative (e.g. fluorescence) data. Notably, ordinal and nominal (e.g. immunostain) non-quantitative data synergize to reduce model uncertainty and improve accuracy. Further, model prediction accuracy and certainty strongly depend on rigorous data-driven formulations of the measurement, and the size and make-up of the datasets. Finally, we demonstrate the potential of a data-driven Measurement Model approach to identify model features that could lead to informative experimental measurements and improve model predictive power.

systems biology↗