Variational embedding of protein folding simulations using Gaussian mixture variational autoencoders

被引:11
|
作者
Ghorbani, Mahdi [1 ,2 ]
Prasad, Samarjeet [1 ]
Klauda, Jeffery B. [2 ]
Brooks, Bernard R. [1 ]
机构
[1] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20824 USA
[2] Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA
来源
JOURNAL OF CHEMICAL PHYSICS | 2021年 / 155卷 / 19期
基金
美国国家科学基金会;
关键词
MARKOV STATE MODELS; MOLECULAR-DYNAMICS SIMULATIONS; TRP-CAGE; KINETICS;
D O I
10.1063/5.0069708
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
Conformational sampling of biomolecules using molecular dynamics simulations often produces a large amount of high dimensional data that makes it difficult to interpret using conventional analysis techniques. Dimensionality reduction methods are thus required to extract useful and relevant information. Here, we devise a machine learning method, Gaussian mixture variational autoencoder (GMVAE), that can simultaneously perform dimensionality reduction and clustering of biomolecular conformations in an unsupervised way. We show that GMVAE can learn a reduced representation of the free energy landscape of protein folding with highly separated clusters that correspond to the metastable states during folding. Since GMVAE uses a mixture of Gaussians as its prior, it can directly acknowledge the multi-basin nature of the protein folding free energy landscape. To make the model end-to-end differentiable, we use a Gumbel-softmax distribution. We test the model on three long-timescale protein folding trajectories and show that GMVAE embedding resembles the folding funnel with folded states down the funnel and unfolded states outside the funnel path. Additionally, we show that the latent space of GMVAE can be used for kinetic analysis and Markov state models built on this embedding produce folding and unfolding timescales that are in close agreement with other rigorous dynamical embeddings such as time independent component analysis.
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页数:11
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