Papers | Pengzhi Zhang

2025

NCOMM
Thor: a platform for cell-level investigation of spatial transcriptomics and histology

Pengzhi Zhang^*, Weiqing Chen^*, Tu N. Tran, Minghao Zhou, Kaylee N. Carter, Ibrahem Kandel, Shengyu Li, Xen Ping Hoi, Yuxing Sun, Li Lai, Keith Youker, Qianqian Song, Yu Yang, Fotis Nikolos, Zejuan Li, Keith Syson Chan, John P. Cooke, and Guangyu Wang

* indicates co-first authors

Nature Communications 2025
Abs Bib 10.1038/s41467-025-62593-1

Spatial transcriptomics links gene expression with tissue morphology, however, current tools often prioritize genomic analysis, lacking integrated image interpretation. To address this, we present Thor, a comprehensive platform for cell-level analysis of spatial transcriptomics and histological images. Thor employs an anti-shrinking Markov diffusion method to infer single-cell spatial transcriptome from spot-level data, effectively combining gene expression and cell morphology. The platform includes 10 modular tools for genomic and image-based analysis, and is paired with Mjolnir, a web-based interface for interactive exploration of gigapixel images. Thor is validated on simulated data and multiple spatial platforms (ISH, MERFISH, Xenium, Stereo-seq). Thor characterizes regenerative signatures in heart failure, screens breast cancer hallmarks, resolves fine layers in mouse olfactory bulb, and annotates fibrotic heart tissue. In high-resolution Visium HD data, it enhances spatial gene patterns aligned with histology. By bridging transcriptomic and histological analysis, Thor enables holistic tissue interpretation in spatial biology.
@article{zhang2025thor-cb3, year = {2025}, title = {Thor: a platform for cell-level investigation of spatial transcriptomics and histology}, author = {Zhang†, Pengzhi and Chen†, Weiqing and Tran, Tu N. and Zhou, Minghao and Carter, Kaylee N. and Kandel, Ibrahem and Li, Shengyu and Hoi, Xen Ping and Sun, Yuxing and Lai, Li and Youker, Keith and Song, Qianqian and Yang, Yu and Nikolos, Fotis and Li, Zejuan and Chan, Keith Syson and Cooke, John P. and Wang, Guangyu}, journal = {Nature Communications}, doi = {10.1038/s41467-025-62593-1}, pages = {7178}, number = {1}, volume = {16}, }
NMETH
A visual–omics foundation model to bridge histopathology with spatial transcriptomics

Weiqing Chen^*, Pengzhi Zhang^*, Tu N Tran, Yiwei Xiao, Shengyu Li, Vrutant V. Shah, Hao Cheng, Kristopher W. Brannan, Keith Youker, Li Lai, Longhou Fang, Yu Yang, Nhat-Tu Le, Jun-ichi Abe, Shu-Hsia Chen, Qin Ma, Ken Chen, Qianqian Song, John P. Cooke, and Guangyu Wang

* indicates co-first authors

Nature Methods 2025
Abs Bib 10.1038/s41592-025-02707-1

Artificial intelligence has revolutionized computational biology. Recent developments in omics technologies, including single-cell RNA sequencing and spatial transcriptomics, provide detailed genomic data alongside tissue histology. However, current computational models focus on either omics or image analysis, lacking their integration. To address this, we developed OmiCLIP, a visual–omics foundation model linking hematoxylin and eosin images and transcriptomics using tissue patches from Visium data. We transformed transcriptomic data into ‘sentences’ by concatenating top-expressed gene symbols from each patch. We curated a dataset of 2.2 million paired tissue images and transcriptomic data across 32 organs to train OmiCLIP integrating histology and transcriptomics. Building on OmiCLIP, our Loki platform offers five key functions: tissue alignment, annotation via bulk RNA sequencing or marker genes, cell-type decomposition, image–transcriptomics retrieval and spatial transcriptomics gene expression prediction from hematoxylin and eosin-stained images. Compared with 22 state-of-the-art models on 5 simulations, and 19 public and 4 in-house experimental datasets, Loki demonstrated consistent accuracy and robustness.
@article{10.1038/s41592-025-02707-1, year = {2025}, title = {A visual–omics foundation model to bridge histopathology with spatial transcriptomics}, author = {Chen†, Weiqing and Zhang†, Pengzhi and Tran, Tu N and Xiao, Yiwei and Li, Shengyu and Shah, Vrutant V. and Cheng, Hao and Brannan, Kristopher W. and Youker, Keith and Lai, Li and Fang, Longhou and Yang, Yu and Le, Nhat-Tu and Abe, Jun-ichi and Chen, Shu-Hsia and Ma, Qin and Chen, Ken and Song, Qianqian and Cooke, John P. and Wang, Guangyu}, journal = {Nature Methods}, issn = {1548-7091}, doi = {10.1038/s41592-025-02707-1}, pmid = {40442373}, pages = {1-15}, }
PS
CaXML: Chemistry‐informed machine learning explains mutual changes between protein conformations and calcium ions in calcium‐binding proteins using structural and topological features

Pengzhi Zhang^*, Jules Nde^*, Yossi Eliaz, Nathaniel Jennings, Piotr Cieplak, and Margaret S. Cheung

* indicates co-first authors

Protein Science 2025
Abs Bib 10.1002/pro.70023

Proteins’ flexibility is a feature in communicating changes in cell signaling instigated by binding with secondary messengers, such as calcium ions, associated with the coordination of muscle contraction, neurotransmitter release, and gene expression. When binding with the disordered parts of a protein, calcium ions must balance their charge states with the shape of calcium‐binding proteins and their versatile pool of partners depending on the circumstances they transmit. Accurately determining the ionic charges of those ions is essential for understanding their role in such processes. However, it is unclear whether the limited experimental data available can be effectively used to train models to accurately predict the charges of calcium‐binding protein variants. Here, we developed a chemistry‐informed, machine‐learning algorithm that implements a game theoretic approach to explain the output of a machine‐learning model without the prerequisite of an excessively large database for high‐performance prediction of atomic charges. We used the ab initio electronic structure data representing calcium ions and the structures of the disordered segments of calcium‐binding peptides with surrounding water molecules to train several explainable models. Network theory was used to extract the topological features of atomic interactions in the structurally complex data dictated by the coordination chemistry of a calcium ion, a potent indicator of its charge state in protein. Our design created a computational tool of CaXML, which provided a framework of explainable machine learning model to annotate ionic charges of calcium ions in calcium‐binding proteins in response to the chemical changes in an environment. Our framework will provide new insights into protein design for engineering functionality based on the limited size of scientific data in a genome space.
@article{zhang2025caxml-ada, year = {2025}, rating = {5}, title = {{CaXML}: Chemistry‐informed machine learning explains mutual changes between protein conformations and calcium ions in calcium‐binding proteins using structural and topological features}, author = {Zhang†, Pengzhi and Nde†, Jules and Eliaz, Yossi and Jennings, Nathaniel and Cieplak, Piotr and Cheung, Margaret S.}, journal = {Protein Science}, issn = {0961-8368}, doi = {10.1002/pro.70023}, pmid = {39865355}, pmcid = {{PMC}11761698}, pages = {e70023}, number = {2}, volume = {34}, }

2024

NMETH

Uncovering cell cycle speed modulations with statistical inference

Pengzhi Zhang, and Guangyu Wang

Nature Methods 2024

@article{10.1038/s41592-024-02484-3,
  year = {2024},
  title = {Uncovering cell cycle speed modulations with statistical inference},
  author = {Zhang, Pengzhi and Wang, Guangyu},
  journal = {Nature Methods},
  issn = {1548-7091},
  doi = {10.1038/s41592-024-02484-3},
  pmid = {39482462},
  pages = {2231-2232},
  number = {12},
  volume = {21},
}

2023

NBT
A relay velocity model infers cell-dependent RNA velocity

Shengyu Li^*, Pengzhi Zhang^*, Weiqing Chen, Lingqun Ye, Kristopher W. Brannan, Nhat-Tu Le, Jun-ichi Abe, John P. Cooke, and Guangyu Wang

* indicates co-first authors

Nature Biotechnology 2023
Abs Bib 10.1038/s41587-023-01728-5

RNA velocity provides an approach for inferring cellular state transitions from single-cell RNA sequencing (scRNA-seq) data. Conventional RNA velocity models infer universal kinetics from all cells in an scRNA-seq experiment, resulting in unpredictable performance in experiments with multi-stage and/or multi-lineage transition of cell states where the assumption of the same kinetic rates for all cells no longer holds. Here we present cellDancer, a scalable deep neural network that locally infers velocity for each cell from its neighbors and then relays a series of local velocities to provide single-cell resolution inference of velocity kinetics. In the simulation benchmark, cellDancer shows robust performance in multiple kinetic regimes, high dropout ratio datasets and sparse datasets. We show that cellDancer overcomes the limitations of existing RNA velocity models in modeling erythroid maturation and hippocampus development. Moreover, cellDancer provides cell-specific predictions of transcription, splicing and degradation rates, which we identify as potential indicators of cell fate in the mouse pancreas. cellDancer enables RNA velocity estimation with cell-specific kinetics.
@article{10.1038/s41587-023-01728-5, year = {2023}, title = {A relay velocity model infers cell-dependent RNA velocity}, author = {Li†, Shengyu and Zhang†, Pengzhi and Chen, Weiqing and Ye, Lingqun and Brannan, Kristopher W. and Le, Nhat-Tu and Abe, Jun-ichi and Cooke, John P. and Wang, Guangyu}, journal = {Nature Biotechnology}, issn = {1087-0156}, doi = {10.1038/s41587-023-01728-5}, pmid = {37012448}, pages = {1-10}, }
JPCB
Experiment and Simulation Reveal Residue Details for How Target Binding Tunes Calmodulin’s Calcium-Binding Properties

Jules Nde, Pengzhi Zhang, M. Neal Waxham, and Margaret S. Cheung

The Journal of Physical Chemistry B 2023
Abs Bib 10.1021/acs.jpcb.2c08734

We aim to elucidate the molecular mechanism of the reciprocal relation of calmodulin’s (CaM) target binding and its affinity for calcium ions (Ca2+), which is central to decoding CaM-dependent Ca2+ signaling in a cell. We employed stopped-flow experiments and coarse-grained molecular simulations that learn the coordination chemistry of Ca2+ in CaM from first-principle calculations. The associative memories as part of the coarse-grained force fields built on known protein structures further influence CaM’s selection of its polymorphic target peptides in the simulations. We modeled the peptides from the Ca2+/CaM-binding domain of Ca2+/CaM-dependent kinase II (CaMKII), CaMKIIp (293–310) and selected distinctive mutations at the N-terminus. Our stopped-flow experiments have shown that the CaM’s affinity for Ca2+ in the bound complex of Ca2+/CaM/CaMKIIp decreased significantly when Ca2+/CaM bound to the mutant peptide (296-AAA-298) compared to that bound to the wild-type peptide (296-RRK-298). The coarse-grained molecular simulations revealed that the 296-AAA-298 mutant peptide destabilized the structures of Ca2+-binding loops at the C-domain of CaM (c-CaM) due to both loss of electrostatic interactions and differences in polymorphic structures. We have leveraged a powerful coarse-grained approach to advance a residue-level understanding of the reciprocal relation in CaM, that could not be possibly achieved by other computational approaches.
@article{10.1021/acs.jpcb.2c08734, year = {2023}, title = {Experiment and Simulation Reveal Residue Details for How Target Binding Tunes Calmodulin’s Calcium-Binding Properties}, author = {Nde, Jules and Zhang, Pengzhi and Waxham, M. Neal and Cheung, Margaret S.}, journal = {The Journal of Physical Chemistry B}, issn = {1520-6106}, doi = {10.1021/acs.jpcb.2c08734}, pmid = {36977372}, pages = {2900-2908}, number = {13}, volume = {127}, }

2022

SciData
Comprehensive spectral libraries for various rabbit eye tissue proteomes.

Guoting Qin, Pengzhi Zhang, Mingxia Sun, Wenjiang Fu, and Chengzhi Cai

Scientific Data 2022
Abs Bib 10.1038/s41597-022-01241-5

Rabbits have been widely used for studying ocular physiology and pathology due to their relatively large eye size and similar structures with human eyes. Various rabbit ocular disease models, such as dry eye, age-related macular degeneration, and glaucoma, have been established. Despite the growing application of proteomics in vision research using rabbit ocular models, there is no spectral assay library for rabbit eye proteome publicly available. Here, we generated spectral assay libraries for rabbit eye compartments, including conjunctiva, cornea, iris, retina, sclera, vitreous humor, and tears using fractionated samples and ion mobility separation enabling deep proteome coverage. The rabbit eye spectral assay library includes 9,830 protein groups and 113,593 peptides. We present the data as a freely available community resource for proteomic studies in the vision field. Instrument data and spectral libraries are available via ProteomeXchange with identifier PXD031194.
@article{10.1038/s41597-022-01241-5, year = {2022}, title = {Comprehensive spectral libraries for various rabbit eye tissue proteomes.}, author = {Qin, Guoting and Zhang, Pengzhi and Sun, Mingxia and Fu, Wenjiang and Cai, Chengzhi}, journal = {Scientific Data}, doi = {10.1038/s41597-022-01241-5}, pmid = {35351915}, pmcid = {PMC8964796}, pages = {111}, number = {1}, volume = {9}, }
JPCL
Correlating Interfacial Charge Transfer Rates with Interfacial Molecular Structure in the Tetraphenyldibenzoperiflanthene/C70 Organic Photovoltaic System

Jacob Tinnin, Srijana Bhandari, Pengzhi Zhang, Eitan Geva, Barry D. Dunietz, Xiang Sun, and Margaret S. Cheung

The Journal of Physical Chemistry Letters 2022
Abs Bib 10.1021/acs.jpclett.1c03618

Organic photovoltaics (OPV) is an emerging solar cell technology that offers vast advantages such as low-cost manufacturing, transparency, and solution processability. However, because the performance of OPV devices is still disappointing compared to their inorganic counterparts, better understanding of how controlling the molecular-level morphology can impact performance is needed. To this end, one has to overcome significant challenges that stem from the complexity and heterogeneity of the underlying electronic structure and molecular morphology. In this Letter, we address this challenge in the context of the DBP/C70 OPV system by employing a modular workflow that combines recent advances in electronic structure, molecular dynamics, and rate theory. We show how the wide range of interfacial pairs can be classified into four types of interfacial donor–acceptor geometries and find that the least populated interfacial geometry gives rise to the fastest charge transfer (CT) rates.
@article{10.1021/acs.jpclett.1c03618, year = {2022}, title = {Correlating Interfacial Charge Transfer Rates with Interfacial Molecular Structure in the Tetraphenyldibenzoperiflanthene/C70 Organic Photovoltaic System}, author = {Tinnin, Jacob and Bhandari, Srijana and Zhang, Pengzhi and Geva, Eitan and Dunietz, Barry D. and Sun, Xiang and Cheung, Margaret S.}, journal = {The Journal of Physical Chemistry Letters}, issn = {1948-7185}, doi = {10.1021/acs.jpclett.1c03618}, pmid = {35040657}, pages = {763-769}, number = {3}, volume = {13}, }

2021

FMOLB
Coarse-Grained Modeling and Molecular Dynamics Simulations of Ca2+-Calmodulin

Jules Nde, Pengzhi Zhang, Jacob C Ezerski, Wei Lu, Kaitlin Knapp, Peter G Wolynes, and Margaret S Cheung

Frontiers in Molecular Biosciences 2021
Abs Bib 10.3389/fmolb.2021.661322

Calmodulin (CaM) is a calcium-binding protein that transduces signals to downstream proteins through target binding upon calcium binding in a time-dependent manner. Understanding the target binding process that tunes CaM’s affinity for the calcium ions (Ca 2+ ), or vice versa, may provide insight into how Ca 2+ -CaM selects its target binding proteins. However, modeling of Ca 2+ -CaM in molecular simulations is challenging because of the gross structural changes in its central linker regions while the two lobes are relatively rigid due to tight binding of the Ca 2+ to the calcium-binding loops where the loop forms a pentagonal bipyramidal coordination geometry with Ca 2+ . This feature that underlies the reciprocal relation between Ca 2+ binding and target binding of CaM, however, has yet to be considered in the structural modeling. Here, we presented a coarse-grained model based on the Associative memory, Water mediated, Structure, and Energy Model (AWSEM) protein force field, to investigate the salient features of CaM. Particularly, we optimized the force field of CaM and that of Ca 2+ ions by using its coordination chemistry in the calcium-binding loops to match with experimental observations. We presented a “community model” of CaM that is capable of sampling various conformations of CaM, incorporating various calcium-binding states, and carrying the memory of binding with various targets, which sets the foundation of the reciprocal relation of target binding and Ca 2+ binding in future studies.
@article{10.3389/fmolb.2021.661322, year = {2021}, title = {Coarse-Grained Modeling and Molecular Dynamics Simulations of Ca2+-Calmodulin}, author = {Nde, Jules and Zhang, Pengzhi and Ezerski, Jacob C and Lu, Wei and Knapp, Kaitlin and Wolynes, Peter G and Cheung, Margaret S}, journal = {Frontiers in Molecular Biosciences}, issn = {2296-889X}, doi = {10.3389/fmolb.2021.661322}, pmid = {34504868}, pmcid = {PMC8421859}, pages = {661322}, volume = {8}, }
JCP
CTRAMER: An open-source software package for correlating interfacial charge transfer rate constants with donor/acceptor geometries in organic photovoltaic materials

Jacob Tinnin, Huseyin Aksu, Zhengqing Tong, Pengzhi Zhang, Eitan Geva, Barry D. Dunietz, Xiang Sun, and Margaret S. Cheung

The Journal of Chemical Physics 2021
Abs Bib 10.1063/5.0050574

In this paper we present CTRAMER (Charge Transfer RAtes from Molecular dynamics, Electronic structure, and Rate theory), an open source software package for calculating interfacial charge transfer (CT) rate constants in organic photovoltaic (OPV) materials based on ab initio calculations and molecular dynamics simulations. The software is based on identifying representative donor acceptor geometries within interfacial structures obtained from molecular dynamics simulation of donor acceptor blends and calculating the corresponding Fermi s golden rule CT rate constants within the framework of the linearized semiclassical approximation. While the methods used are well established, the integration of these state of the art ideas from different disciplines to study photoinduced CT between excited states and explicit environment, in our opinion, makes this package unique and innovative. The software also provides tools for plotting other observables of interest. After outlining the features and implementation details, usage and performance of the software are demonstrated with results from an example OPV system.
@article{10.1063/5.0050574, year = {2021}, title = {CTRAMER: An open-source software package for correlating interfacial charge transfer rate constants with donor/acceptor geometries in organic photovoltaic materials}, author = {Tinnin, Jacob and Aksu, Huseyin and Tong, Zhengqing and Zhang, Pengzhi and Geva, Eitan and Dunietz, Barry D. and Sun, Xiang and Cheung, Margaret S.}, journal = {The Journal of Chemical Physics}, issn = {0021-9606}, doi = {10.1063/5.0050574}, eprint = {2105.05936}, pages = {214108}, number = {21}, volume = {154}, }
JCP
Determining the atomic charge of calcium ion requires the information of its coordination geometry in an EF-hand motif

Pengzhi Zhang, Jaebeom Han, Piotr Cieplak, and Margaret S. Cheung

The Journal of Chemical Physics 2021
Abs Bib 10.1063/5.0037517

It is challenging to parameterize the force field for calcium ions (Ca2+) in calcium-binding proteins because of their unique coordination chemistry that involves the surrounding atoms required for stability. In this work, we observed wide variation in Ca2+ binding loop conformations of the Ca2+-binding protein calmodulin (CaM), which adopts the most populated ternary structures determined from the MD simulations, followed by ab initio quantum mechanical (QM) calculations on all twelve amino acids in the loop that coordinate Ca2+ in aqueous solution. Ca2+ charges were derived by fitting to the electrostatic potential (ESP) in the context of a classical or polarizable force field (PFF). We discovered that the atomic radius of Ca2+ in conventional force fields is too large for the QM calculation to capture the variation in the coordination geometry of Ca2+ in its ionic form, leading to unphysical charges. Specifically, we found that the fitted atomic charges of Ca2+ in the context of PFF depend on the coordinating geometry of electronegative atoms from the amino acids in the loop. Although nearby water molecules do not influence the atomic charge of Ca2+, they are crucial for compensating for the coordination of Ca2+ due to the conformational flexibility in the EF-hand loop. Our method advances the development of force fields for metal ions and protein binding sites in dynamic environments.
@article{10.1063/5.0037517, year = {2021}, title = {Determining the atomic charge of calcium ion requires the information of its coordination geometry in an EF-hand motif}, author = {Zhang, Pengzhi and Han, Jaebeom and Cieplak, Piotr and Cheung, Margaret S.}, journal = {The Journal of Chemical Physics}, issn = {0021-9606}, doi = {10.1063/5.0037517}, eprint = {2011.07639}, pages = {124104}, number = {12}, volume = {154}, }

2020

BPJ
Molecular Dynamics Ensemble Refinement of Intrinsically Disordered Peptides According to Deconvoluted Spectra from Circular Dichroism

Jacob C. Ezerski, Pengzhi Zhang, Nathaniel C. Jennings, M. Neal Waxham, and Margaret S. Cheung

Biophysical Journal 2020
Abs Bib PDF 10.1016/j.bpj.2020.02.015

We have developed a computational method of atomistically refining the structural ensemble of intrinsically disordered peptides (IDPs) facilitated by experimental measurements using circular dichroism spectroscopy (CD). A major challenge surrounding this approach stems from the deconvolution of experimental CD spectra into secondary structure features of the IDP ensemble. Currently available algorithms for CD deconvolution were designed to analyze the spectra of proteins with stable secondary structures. Herein, our work aims to minimize any bias from the peptide deconvolution analysis by implementing a non-negative linear least-squares fitting algorithm in conjunction with a CD reference data set that contains soluble and denatured proteins (SDP48). The non-negative linear least-squares method yields the best results for deconvolution of proteins with higher disordered content than currently available methods, according to a validation analysis of a set of protein spectra with Protein Data Bank entries. We subsequently used this analysis to deconvolute our experimental CD data to refine our computational model of the peptide secondary structure ensemble produced by all-atom molecular dynamics simulations with implicit solvent. We applied this approach to determine the ensemble structures of a set of short IDPs, that mimic the calmodulin binding domain of calcium/calmodulin-dependent protein kinase II and its 1-amino-acid and 3-amino-acid mutants. Our study offers a, to our knowledge, novel way to solve the ensemble secondary structures of IDPs in solution, which is important to advance the understanding of their roles in regulating signaling pathways through the formation of complexes with multiple partners.
@article{10.1016/j.bpj.2020.02.015, year = {2020}, title = {Molecular Dynamics Ensemble Refinement of Intrinsically Disordered Peptides According to Deconvoluted Spectra from Circular Dichroism}, author = {Ezerski, Jacob C. and Zhang, Pengzhi and Jennings, Nathaniel C. and Waxham, M. Neal and Cheung, Margaret S.}, journal = {Biophysical Journal}, issn = {0006-3495}, doi = {10.1016/j.bpj.2020.02.015}, pmid = {32145192}, pages = {1665-1678}, number = {7}, volume = {118}, }
JCTC
On the Interplay between Electronic Structure and Polarizable Force Fields When Calculating Solution-Phase Charge-Transfer Rates

Jaebeom Han, Pengzhi Zhang, Huseyin Aksu, Buddhadev Maiti, Xiang Sun, Eitan Geva, Barry D. Dunietz, and Margaret S. Cheung

Journal of Chemical Theory and Computation 2020
Abs Bib 10.1021/acs.jctc.0c00796

We present a comprehensive analysis of the interplay between the choice of an electronic structure method and the effect of using polarizable force fields vs. nonpolarizable force fields when calculating solution-phase charge-transfer (CT) rates. The analysis is based on an integrative approach that combines inputs from electronic structure calculations and molecular dynamics simulations and is performed in the context of the carotenoid-porphyrin-C60 molecular triad dissolved in an explicit tetrahydrofuran (THF) liquid solvent. Marcus theory rate constants are calculated for the multiple CT processes that occur in this system based on either polarizable or nonpolarizable force fields, parameterized using density functional theory (DFT) with either the B3LYP or the Baer-Neuhauser-Livshits (BNL) density functionals. We find that the effect of switching from nonpolarizable to polarizable force fields on the CT rates is strongly dependent on the choice of the density functional. More specifically, the rate constants obtained using polarizable and nonpolarizable force fields differ significantly when B3LYP is used, while much smaller changes are observed when BNL is used. It is shown that this behavior can be traced back to the tendency of B3LYP to overstabilize CT states, thereby pushing the underlying electronic transitions to the deep inverted region, where even small changes in the force fields can lead to significant changes in the CT rate constants. Our results demonstrate the importance of combining polarizable force fields with an electronic structure method that can accurately capture the energies of excited CT states when calculating charge-transfer rates.
@article{10.1021/acs.jctc.0c00796, year = {2020}, title = {On the Interplay between Electronic Structure and Polarizable Force Fields When Calculating Solution-Phase Charge-Transfer Rates}, author = {Han, Jaebeom and Zhang, Pengzhi and Aksu, Huseyin and Maiti, Buddhadev and Sun, Xiang and Geva, Eitan and Dunietz, Barry D. and Cheung, Margaret S.}, journal = {Journal of Chemical Theory and Computation}, issn = {1549-9618}, doi = {10.1021/acs.jctc.0c00796}, pmid = {32997944}, pages = {6481-6490}, number = {10}, volume = {16}, }
PRApplied
Molecular-Level Exploration of the Structure-Function Relations Underlying Interfacial Charge Transfer in the Subphthalocyanine/C60 Organic Photovoltaic System

Jacob Tinnin, Srijana Bhandari, Pengzhi Zhang, Huseyin Aksu, Buddhadev Maiti, Eitan Geva, Barry D. Dunietz, Xiang Sun, and Margaret S. Cheung

Physical Review Applied 2020
Abs Bib 10.1103/physrevapplied.13.054075

The arrangement of organic molecules at the donor-acceptor interface in an organic photovoltaic (OPV) cell can have a strong effect on the generation of charge carriers and thereby cell performance. In this paper, we report the molecular-level exploration of the ensemble of interfacial donor-acceptor pair geometries and the charge-transfer (CT) rates to which they give rise. Our approach combines molecular-dynamics simulations, electronic structure calculations, machine learning, and rate theory. This approach is applied to the boron subphthalocyanine chloride (donor) and C60 (acceptor) OPV system. We find that the interface is dominated by a previously unreported donor-acceptor pair edge geometry, which contributes significantly to device performance in a manner that depends on the initial conditions. Quantitative relations between the morphology and CT rates are established, which can be used to advance the design of more efficient OPV devices.
@article{10.1103/physrevapplied.13.054075, year = {2020}, title = {Molecular-Level Exploration of the Structure-Function Relations Underlying Interfacial Charge Transfer in the Subphthalocyanine/C60 Organic Photovoltaic System}, author = {Tinnin, Jacob and Bhandari, Srijana and Zhang, Pengzhi and Aksu, Huseyin and Maiti, Buddhadev and Geva, Eitan and Dunietz, Barry D. and Sun, Xiang and Cheung, Margaret S.}, journal = {Physical Review Applied}, doi = {10.1103/physrevapplied.13.054075}, pages = {054075}, number = {5}, volume = {13}, }

2018

JPCC

Computational Study of Charge-Transfer Dynamics in the Carotenoid–Porphyrin–C 60 Molecular Triad Solvated in Explicit Tetrahydrofuran and Its Spectroscopic Signature

Xiang Sun, Pengzhi Zhang, Yifan Lai, Kyle L Williams, Margaret S. Cheung, Barry D. Dunietz, and Eitan Geva

The Journal of Physical Chemistry C 2018

Bib 10.1021/acs.jpcc.8b02697

@article{10.1021/acs.jpcc.8b02697,
  year = {2018},
  title = {Computational Study of Charge-Transfer Dynamics in the Carotenoid–Porphyrin–C 60 Molecular Triad Solvated in Explicit Tetrahydrofuran and Its Spectroscopic Signature},
  author = {Sun, Xiang and Zhang, Pengzhi and Lai, Yifan and Williams, Kyle L and Cheung, Margaret S. and Dunietz, Barry D. and Geva, Eitan},
  journal = {The Journal of Physical Chemistry C},
  issn = {1932-7447},
  doi = {10.1021/acs.jpcc.8b02697},
  pages = {11288-11299},
  number = {21},
  volume = {122},
}

2017

PCCP
Induced polarization restricts the conformational distribution of a light-harvesting molecular triad in the ground state

Oleg N. Starovoytov, Pengzhi Zhang, Piotr Cieplak, and Margaret S. Cheung

Physical Chemistry Chemical Physics 2017
Abs Bib 10.1039/c7cp03177g

The light-harvesting molecular triad consisting of carotenoid polyene (C), diaryl-porphyrin (P) and pyrrole-fullerene (C60) is a donor–acceptor molecule capable of absorbing incident light in the visible range. Its ability to convert solar energy to electrical excitation and charge separation energy suggests a great potential in real-world applications. The ensemble of its conformations under ambient conditions varies widely according to its electronic state. In previous work, we applied a non-polarizable model to study the conformational distribution of the molecular triad in the ground and charge separated states. However, due to the lack of polarization, which imparts subtle changes in the charge distribution on atoms, molecular simulations fail to produce accurate average dipole moments. We developed the first polarizable model for a molecular triad to investigate the structural and dynamic properties of a molecular triad in the ground state in an explicit organic solvent, tetrahydrofuran (THF). We performed first-principles electronic structure calculations of the individual components in the triad as well as THF and then fit the partial atomic charges to the electrostatic potential using the i-RESP methodology. We validated these force field parameters by comparing the thermodynamic and dynamic properties obtained from molecular dynamics simulations with those from experiments. We enhanced the sampling of the triad conformations with replica exchange molecular dynamics simulations. We characterized the effects of induced polarization on the structural stability of the triad by analyzing the free energy landscapes constructed with polarizable force fields. Furthermore, by using principal component analysis, we found that the molecular triad conformations adopted a small range of torsional angles with induced polarization. The triad conformation solvated in polar solvent with a polarizable force field qualitatively agrees with that obtained from nuclear magnetic resonance spectroscopy.
@article{10.1039/c7cp03177g, year = {2017}, title = {Induced polarization restricts the conformational distribution of a light-harvesting molecular triad in the ground state}, author = {Starovoytov, Oleg N. and Zhang, Pengzhi and Cieplak, Piotr and Cheung, Margaret S.}, journal = {Physical Chemistry Chemical Physics}, issn = {1463-9076}, doi = {10.1039/c7cp03177g}, pmid = {28815237}, pages = {22969-22980}, number = {34}, volume = {19}, }
BPJ
Opposing Intermolecular Tuning of Ca2+ Affinity for Calmodulin by Neurogranin and CaMKII Peptides

Pengzhi Zhang, Swarnendu Tripathi, Hoa Trinh, and Margaret S. Cheung

Biophysical Journal 2017
Abs Bib 10.1016/j.bpj.2017.01.020

We investigated the impact of bound calmodulin (CaM)-target compound structure on the affinity of calcium (Ca2+) by integrating coarse-grained models and all-atomistic simulations with nonequilibrium physics. We focused on binding between CaM and two specific targets, Ca2+/CaM-dependent protein kinase II (CaMKII) and neurogranin (Ng), as they both regulate CaM-dependent Ca2+ signaling pathways in neurons. It was shown experimentally that Ca2+/CaM (holoCaM) binds to the CaMKII peptide with overwhelmingly higher affinity than Ca2+-free CaM (apoCaM); the binding of CaMKII peptide to CaM in return increases the Ca2+ affinity for CaM. However, this reciprocal relation was not observed in the Ng peptide (Ng13–49), which binds to apoCaM or holoCaM with binding affinities of the same order of magnitude. Unlike the holoCaM-CaMKII peptide, whose structure can be determined by crystallography, the structural description of the apoCaM-Ng13–49 is unknown due to low binding affinity, therefore we computationally generated an ensemble of apoCaM-Ng13–49 structures by matching the changes in the chemical shifts of CaM upon Ng13–49 binding from nuclear magnetic resonance experiments. Next, we computed the changes in Ca2+ affinity for CaM with and without binding targets in atomistic models using Jarzynski’s equality. We discovered the molecular underpinnings of lowered affinity of Ca2+ for CaM in the presence of Ng13–49 by showing that the N-terminal acidic region of Ng peptide pries open the β-sheet structure between the Ca2+ binding loops particularly at C-domain of CaM, enabling Ca2+ release. In contrast, CaMKII peptide increases Ca2+ affinity for the C-domain of CaM by stabilizing the two Ca2+ binding loops. We speculate that the distinctive structural difference in the bound complexes of apoCaM-Ng13–49 and holoCaM-CaMKII delineates the importance of CaM’s progressive mechanism of target binding on its Ca2+ binding affinities.
@article{10.1016/j.bpj.2017.01.020, year = {2017}, title = {Opposing Intermolecular Tuning of Ca2+ Affinity for Calmodulin by Neurogranin and CaMKII Peptides}, author = {Zhang, Pengzhi and Tripathi, Swarnendu and Trinh, Hoa and Cheung, Margaret S.}, journal = {Biophysical Journal}, issn = {0006-3495}, doi = {10.1016/j.bpj.2017.01.020}, pmid = {28355539}, pages = {1105-1119}, number = {6}, volume = {112}, }

2015

JMR
Conformational frustration in calmodulin–target recognition

Swarnendu Tripathi, Qian Wang, Pengzhi Zhang, Laurel Hoffman, M. Neal Waxham, and Margaret S. Cheung

Journal of Molecular Recognition 2015
Abs Bib 10.1002/jmr.2413

Calmodulin (CaM) is a primary calcium (Ca2+)-signaling protein that specifically recognizes and activates highly diverse target proteins. We explored the molecular basis of target recognition of CaM with peptides representing the CaM-binding domains from two Ca2+-CaM-dependent kinases, CaMKI and CaMKII, by employing experimentally constrained molecular simulations. Detailed binding route analysis revealed that the two CaM target peptides, although similar in length and net charge, follow distinct routes that lead to a higher binding frustration in the CaM–CaMKII complex than in the CaM–CaMKI complex. We discovered that the molecular origin of the binding frustration is caused by intermolecular contacts formed with the C-domain of CaM that need to be broken before the formation of intermolecular contacts with the N-domain of CaM. We argue that the binding frustration is important for determining the kinetics of the recognition process of proteins involving large structural fluctuations. Copyright © 2015 John Wiley & Sons, Ltd.
@article{10.1002/jmr.2413, year = {2015}, title = {Conformational frustration in calmodulin–target recognition}, author = {Tripathi, Swarnendu and Wang, Qian and Zhang, Pengzhi and Hoffman, Laurel and Waxham, M. Neal and Cheung, Margaret S.}, journal = {Journal of Molecular Recognition}, issn = {1099-1352}, doi = {10.1002/jmr.2413}, pmid = {25622562}, pmcid = {PMC4477201}, pages = {74-86}, number = {2}, volume = {28}, }

2013

Protein recognition and selection through conformational and mutually induced fit

Qian Wang^*, Pengzhi Zhang^*, Laurel Hoffman, Swarnendu Tripathi, Dirar Homouz, Yin Liu, M. Neal Waxham, and Margaret S. Cheung

* indicates co-first authors

Proceedings of the National Academy of Sciences 2013
Abs Bib 10.1073/pnas.1312788110

Protein–protein interactions drive most every biological process, but in many instances the domains mediating recognition are disordered. How specificity in binding is attained in the absence of defined structure contrasts with well-established experimental and theoretical work describing ligand binding to protein. The signaling protein calmodulin presents a unique opportunity to investigate mechanisms for target recognition given that it interacts with several hundred different targets. By advancing coarse-grained computer simulations and experimental techniques, mechanistic insights were gained in defining the pathways leading to recognition and in how target selectivity can be achieved at the molecular level. A model requiring mutually induced conformational changes in both calmodulin and target proteins was necessary and broadly informs how proteins can achieve both high affinity and high specificity.
@article{10.1073/pnas.1312788110, year = {2013}, title = {Protein recognition and selection through conformational and mutually induced fit}, author = {Wang†, Qian and Zhang†, Pengzhi and Hoffman, Laurel and Tripathi, Swarnendu and Homouz, Dirar and Liu, Yin and Waxham, M. Neal and Cheung, Margaret S.}, journal = {Proceedings of the National Academy of Sciences}, issn = {0027-8424}, doi = {10.1073/pnas.1312788110}, pmid = {24297894}, pmcid = {PMC3870683}, pages = {20545-20550}, number = {51}, volume = {110}, }