10 research outputs found
Transferable neural networks for enhanced sampling of protein dynamics
Variational auto-encoder frameworks have demonstrated success in reducing
complex nonlinear dynamics in molecular simulation to a single non-linear
embedding. In this work, we illustrate how this non-linear latent embedding can
be used as a collective variable for enhanced sampling, and present a simple
modification that allows us to rapidly perform sampling in multiple related
systems. We first demonstrate our method is able to describe the effects of
force field changes in capped alanine dipeptide after learning a model using
AMBER99. We further provide a simple extension to variational dynamics encoders
that allows the model to be trained in a more efficient manner on larger
systems by encoding the outputs of a linear transformation using time-structure
based independent component analysis (tICA). Using this technique, we show how
such a model trained for one protein, the WW domain, can efficiently be
transferred to perform enhanced sampling on a related mutant protein, the GTT
mutation. This method shows promise for its ability to rapidly sample related
systems using a single transferable collective variable and is generally
applicable to sets of related simulations, enabling us to probe the effects of
variation in increasingly large systems of biophysical interest.Comment: 20 pages, 10 figure
Deep learning models for predicting RNA degradation via dual crowdsourcing
Medicines based on messenger RNA (mRNA) hold immense potential, as evidenced by their rapid deployment as COVID-19 vaccines. However, worldwide distribution of mRNA molecules has been limited by their thermostability, which is fundamentally limited by the intrinsic instability of RNA molecules to a chemical degradation reaction called in-line hydrolysis. Predicting the degradation of an RNA molecule is a key task in designing more stable RNA-based therapeutics. Here, we describe a crowdsourced machine learning competition (‘Stanford OpenVaccine’) on Kaggle, involving single-nucleotide resolution measurements on 6,043 diverse 102–130-nucleotide RNA constructs that were themselves solicited through crowdsourcing on the RNA design platform Eterna. The entire experiment was completed in less than 6 months, and 41% of nucleotide-level predictions from the winning model were within experimental error of the ground truth measurement. Furthermore, these models generalized to blindly predicting orthogonal degradation data on much longer mRNA molecules (504–1,588 nucleotides) with improved accuracy compared with previously published models. These results indicate that such models can represent in-line hydrolysis with excellent accuracy, supporting their use for designing stabilized messenger RNAs. The integration of two crowdsourcing platforms, one for dataset creation and another for machine learning, may be fruitful for other urgent problems that demand scientific discovery on rapid timescales
Deep learning models for predicting RNA degradation via dual crowdsourcing
Messenger RNA-based medicines hold immense potential, as evidenced by their
rapid deployment as COVID-19 vaccines. However, worldwide distribution of mRNA
molecules has been limited by their thermostability, which is fundamentally
limited by the intrinsic instability of RNA molecules to a chemical degradation
reaction called in-line hydrolysis. Predicting the degradation of an RNA
molecule is a key task in designing more stable RNA-based therapeutics. Here,
we describe a crowdsourced machine learning competition ("Stanford
OpenVaccine") on Kaggle, involving single-nucleotide resolution measurements on
6043 102-130-nucleotide diverse RNA constructs that were themselves solicited
through crowdsourcing on the RNA design platform Eterna. The entire experiment
was completed in less than 6 months, and 41% of nucleotide-level predictions
from the winning model were within experimental error of the ground truth
measurement. Furthermore, these models generalized to blindly predicting
orthogonal degradation data on much longer mRNA molecules (504-1588
nucleotides) with improved accuracy compared to previously published models.
Top teams integrated natural language processing architectures and data
augmentation techniques with predictions from previous dynamic programming
models for RNA secondary structure. These results indicate that such models are
capable of representing in-line hydrolysis with excellent accuracy, supporting
their use for designing stabilized messenger RNAs. The integration of two
crowdsourcing platforms, one for data set creation and another for machine
learning, may be fruitful for other urgent problems that demand scientific
discovery on rapid timescales
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Predicting multiple conformations via sequence clustering and AlphaFold2.
AlphaFold2 (ref. 1) has revolutionized structural biology by accurately predicting single structures of proteins. However, a protein's biological function often depends on multiple conformational substates2, and disease-causing point mutations often cause population changes within these substates3,4. We demonstrate that clustering a multiple-sequence alignment by sequence similarity enables AlphaFold2 to sample alternative states of known metamorphic proteins with high confidence. Using this method, named AF-Cluster, we investigated the evolutionary distribution of predicted structures for the metamorphic protein KaiB5 and found that predictions of both conformations were distributed in clusters across the KaiB family. We used nuclear magnetic resonance spectroscopy to confirm an AF-Cluster prediction: a cyanobacteria KaiB variant is stabilized in the opposite state compared with the more widely studied variant. To test AF-Cluster's sensitivity to point mutations, we designed and experimentally verified a set of three mutations predicted to flip KaiB from Rhodobacter sphaeroides from the ground to the fold-switched state. Finally, screening for alternative states in protein families without known fold switching identified a putative alternative state for the oxidoreductase Mpt53 in Mycobacterium tuberculosis. Further development of such bioinformatic methods in tandem with experiments will probably have a considerable impact on predicting protein energy landscapes, essential for illuminating biological function
Surface and Stability Characterization of a Nanoporous ZIF‑8 Thin Film
Zeolitic imidazolate frameworks (ZIFs)
have been widely investigated
for numerous applications including energy storage, heterogeneous
catalysis, and greenhouse gas adsorption. Much of the early work has
focused on the bulk properties of microcrystalline ZIFs. Herein, we
focus on identifying the nature of the surface of ZIF-8 by studying
a supported ZIF-8 nanoparticle film using surface characterization
techniques. We have experimentally identified the presence of a zinc-rich
surface terminated by carbonates and water/hydroxyl groups (in addition
to the expected methylimidazole terminations) using X-ray photoelectron
spectroscopy (XPS). The thermal stability of ZIF-8 thin films was
also investigated using scanning electron microscopy (SEM) and temperature-programmed
reaction spectroscopy (TPRS). We determined the onset of decomposition
of ZIF-8 thin films to be approximately 630 K using TPRS in an ultrahigh
vacuum (UHV) environment. This work presents the first characterization
steps needed to study the evolution of ZIF surfaces in situ using
surface characterization techniques. Such techniques are capable of
determining reaction products and tracking intermediates and surface
evolution in gas adsorption/reaction studies of thin films