A Data‐Driven Accelerated Sampling Method for Searching Functional States of Proteins

Zhu, Qunzhi; Yuan, Yigao; Ma, Jing; Dong, Hao

doi:10.1002/adts.201800171

Cited by 6 publications

(9 citation statements)

References 74 publications

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“…To more quantitatively characterize the activation dynamics of the two S-proteins, we conducted umbrella sampling simulations starting from the structures along the transition pathways by the above PaCS-MD simulations. As demonstrated in previous works, − the PaCS-MD simulations can sample more realistic transition pathways compared to other methods with biasing potential and the umbrella sampling simulations initiating from the structures sampled by PaCS-MD simulations can cover the conformational space relevant to the conformational transition, which is essential for accurate estimation of the free energy landscapes. More details of the umbrella simulations are given in the Materials and Methods section.…”

Section: Resultsmentioning

confidence: 96%

Activation Pathways and Free Energy Landscapes of the SARS-CoV-2 Spike Protein

Qian

Yang

et al. 2021

ACS Omega

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses a spike protein (S-protein) to recognize the receptor protein ACE2 of human cells and initiate infection, during which the conformational transition of the S-protein from inactive (down) state to active (up) state is one of the key molecular events determining the infectivity but the underlying mechanism remains poorly understood. In this work, we investigated the activation pathways and free energy landscape of the S-protein of SARS-CoV-2 and compared with those of the closely related counterpart SARS-CoV using molecular dynamics simulations. Our results revealed a large difference between the activation pathways of the two S-proteins. The transition from inactive to an active state for the S-protein of SARS-CoV-2 is more cooperative, involving simultaneous disruptions of several key interfacial hydrogen bonds, and the transition encounters a much higher free energy barrier. In addition, the conformational equilibrium of the SARS-CoV-2 S-protein is more biased to the inactive state compared to that of the SARS-CoV S-protein, suggesting the transient feature of the active state before binding to the receptor protein of the host cell. The key interactions contributing to the difference of the activation pathways and free energy landscapes were discussed. The results provide insights into the molecular mechanism involved in the initial stage of the SARS-CoV-2 infection.

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Section: Resultsmentioning

confidence: 96%

Activation Pathways and Free Energy Landscapes of the SARS-CoV-2 Spike Protein

Qian

Yang

et al. 2021

ACS Omega

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“…Previously, we proposed a DA2 protocol to identify unknown functional states starting from a known state . With DA2, the conformational change of protein was driven along the favorable pathways by following its intrinsic motions.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we proposed a data-driven accelerated (DA2) sampling method to drive the conformational change of protein along its intrinsic motion without introducing biased potential/force, where the highly redundant configuration information generated by MD simulations were reduced through adaptively updated feature space by applying PCA at each cycle of computations . Here feature space mainly retains information that most relevant to conformational changes; therefore, DA2 could be used to search for an unknown state structure of protein from a known one.…”

Section: Introductionmentioning

confidence: 99%

“…23 Previously, we proposed a data-driven accelerated (DA2) sampling method to drive the conformational change of protein along its intrinsic motion without introducing biased potential/ force, where the highly redundant configuration information generated by MD simulations were reduced through adaptively updated feature space by applying PCA at each cycle of computations. 24 Here feature space mainly retains information that most relevant to conformational changes; therefore, DA2 could be used to search for an unknown state structure of protein from a known one. By using a similar idea, in this work, we proposed a two-ended data-driven accelerated (teDA2) protocol, which was designed to unbiasedly explore the relevant phase space of the conformational transition between two welldefined functional states more efficiently.…”

Section: ■ Introductionmentioning

confidence: 99%

“…55 ■ METHODOLOGY Previously, we proposed a DA2 protocol to identify unknown functional states starting from a known state. 24 With DA2, the conformational change of protein was driven along the favorable pathways by following its intrinsic motions. On the basis of the same ideas, a teDA2 method was further developed to explore the transition pathways between two known states with high efficiency and accuracy.…”

Section: ■ Introductionmentioning

confidence: 99%

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A Two-Ended Data-Driven Accelerated Sampling Method for Exploring the Transition Pathways between Two Known States of Protein

Yuan

Zhu

Song

et al. 2020

J. Chem. Theory Comput.

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Conformational transitions of protein between different states are often associated with their biological functions. These dynamic processes, however, are usually not easy to be well characterized by experimental measurements, mainly because of inadequate temporal and spatial resolution. Meantime, sampling of configuration space with molecular dynamics (MD) simulations is still a challenge. Here we proposed a robust two-ended data-driven accelerated (teDA2) conformational sampling method, which drives the structural change in an adaptively updated feature space without introducing a bias potential. teDA2 was applied to explore adenylate kinase (ADK), a model with well characterized “open” and “closed” states. A single conformational transition event of ADK could be achieved within only a few or tens of nanoseconds sampled with teDA2. By analyzing hundreds of transition events, we reproduced different mechanisms and the associated pathways for domain motion of ADK reported in the literature. The multiroute characteristic of ADK was confirmed by the fact that some metastable states identified with teDA2 resemble available crystal structures determined at different conditions. This feature was further validated with Markov state modeling with independent MD simulations. Therefore, our work provides strong evidence for the conformational plasticity of protein, which is mainly due to the inherent degree of flexibility. As a reliable and efficient enhanced sampling protocol, teDA2 could be used to study the dynamics between functional states of various biomolecular machines.

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Treating Polarization Effects in Charged and Polar Bio-Molecules Through Variable Electrostatic Parameters

Zhu

et al. 2023

J. Chem. Theory Comput.

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Polarization plays important roles in charged and hydrogen bonding containing systems. Much effort ranging from the construction of physics-based models to quantum mechanism (QM)-based and machine learning (ML)-assisted models have been devoted to incorporating the polarization effect into the conventional force fields at different levels, such as atomic and coarse grained (CG). The application of polarizable force fields or polarization models was limited by two aspects, namely, computational cost and transferability. Different from physics-based models, no predetermining parameters were required in the QM-based approaches. Taking advantage of both the accuracy of QM calculations and efficiency of molecular mechanism (MM) and ML, polarization effects could be treated more efficiently while maintaining the QM accuracy. The computational cost could be reduced with variable electrostatic parameters, such as the charge, dipole, and electronic dielectric constant with the help of linear scaling fragmentation-based QM calculations and ML models. Polarization and entropy effects on the prediction of partition coefficient of druglike molecules are demonstrated by using both explicit or implicit all-atom molecular dynamics simulations and machine learning-assisted models. Directions and challenges for future development are also envisioned.

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A Data‐Driven Accelerated Sampling Method for Searching Functional States of Proteins

Cited by 6 publications

References 74 publications

Activation Pathways and Free Energy Landscapes of the SARS-CoV-2 Spike Protein

Activation Pathways and Free Energy Landscapes of the SARS-CoV-2 Spike Protein

A Two-Ended Data-Driven Accelerated Sampling Method for Exploring the Transition Pathways between Two Known States of Protein

Treating Polarization Effects in Charged and Polar Bio-Molecules Through Variable Electrostatic Parameters

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