Combining Docking Pose Rank and Structure with Deep Learning Improves Protein-Ligand Binding Mode Prediction over a Baseline Docking Approach
Joseph A. Morrone, Jeffrey K. Weber, Tien Huynh, Heng Luo, Wendy D. Cornell
Journal of Chemical Information and Modeling 60(9), 4170-4179, 2020
We present a simple, modular graph-based convolutional neural network that takes structural information from protein-ligand complexes as input to generate models for activity and binding mode
prediction. Complex structures are generated by a standard docking procedure and fed into a dual-graph architecture that includes separate subnetworks for the ligand bonded topology and the ligand-protein contact map. Recent work has indicated that data set bias drives many past promising results derived from combining deep learning and docking. Our dual-graph network allows contributions from ligand identity that give rise to such biases to be distinguished from effects of protein-ligand interactions on classification. We show that our neural network is capable of learning from protein structural information when, as in the case of binding mode prediction, an unbiased data set is constructed. We next develop a deep learning model for binding mode prediction that uses docking ranking as input in combination with docking structures. This strategy mirrors past consensus models and outperforms a baseline docking program (AutoDock Vina) in a variety of tests, including on cross-docking data sets that mimic real-world docking use cases. Furthermore, the magnitudes of network predictions serve as reliable measures of model confidence.
HIV-1 induced changes in HLA-C*03 : 04-presented peptide repertoires lead to reduced engagement of inhibitory natural killer cell receptors
Maja C. Ziegler, Annika Nelde, Jeffrey K. Weber, Christian M. Schreitmuller, Gloria Martrus, Tien Huynh, Madeleine J. Bunders, Sebastian Lunemann, Stefan Stevanovic, Ruhong Zhou, Marcus Altfeld
AIDS 34(12), 1713-1723, 2020
Abstract natural killer cell, receptor, peptide, human leukocyte antigen, hla c, intracellular, cell, tandem mass spectrometry, cell biology, chemistry
OBJECTIVE: Viral infections influence intracellular peptide repertoires available for presentation by HLA-I. Alterations in HLA-I/peptide complexes can modulate binding of killer immunoglobuline-like receptors (KIRs) and thereby the function of natural killer (NK) cells. Although multiple studies have provided evidence that HLA-I/KIR interactions play a role in HIV-1 disease progression, the consequence of HIV-1 infection for HLA-I/KIR interactions remain largely unknown. DESIGN: We determined changes in HLA-I presented peptides resulting from HIV-1-infection of primary human CD4 T cells and assessed the impact of changes in peptide repertoires on HLA-I/KIR interactions. METHODS: Liquid chromatography-coupled tandem mass spectrometry to identify HLA-I presented peptides, cell-based in-vitro assays to evaluate functional consequences of alterations in immunopeptidome and atomistic molecular dynamics simulations to confirm experimental data. RESULTS: A total of 583 peptides exclusively presented on HIV-1-infected cells were identified, of which only 0.2% represented HIV-1 derived peptides. Focusing on HLA-C*03:04/KIR2DL3 interactions, we observed that HLA-C*03:04-presented peptides derived from noninfected CD4 T cells mediated stronger binding of inhibitory KIR2DL3 than peptides derived from HIV-1-infected cells. Furthermore, the most abundant peptide presented by HLA-C*03:04 on noninfected CD4 T cells (VIYPARISL) mediated the strongest KIR2DL3-binding, while the most abundant peptide presented on HIV-1-infected cells (YAIQATETL) did not mediate KIR2DL3-binding. Molecular dynamics simulations of HLA-C*03:04/KIR2DL3 interactions in the context of these two peptides revealed that VIYPARISL significantly enhanced the HLA-C*03:04/peptide contact area to KIR2DL3 compared with YAIQATETL. CONCLUSION: These data demonstrate that HIV-1 infection-induced changes in HLA-I-presented peptides can reduce engagement of inhibitory KIRs, providing a mechanism for enhanced activation of NK cells by virus-infected cells.
natural killer cell, receptor, peptide, human leukocyte antigen, hla c, intracellular, cell, tandem mass spectrometry, cell biology, chemistry
In silico design and validation of high-affinity RNA aptamers targeting epithelial cellular adhesion molecule dimers
David R Bell, Jeffrey K Weber, Wang Yin, Tien Huynh, Wei Duan, Ruhong Zhou
Proceedings of the National Academy of Sciences of the United States of America 117(15), 8486-8493, 2020
Abstract aptamer, systematic evolution of ligands by exponential enrichment, in silico, virtual screening, rational design, isothermal titration calorimetry, docking, nucleic acid, computational biology, chemistry
Nucleic acid aptamers hold great promise for therapeutic applications due to their favorable intrinsic properties, as well as high-throughput experimental selection techniques. Despite the utility of the systematic evolution of ligands by the exponential enrichment (SELEX) method for aptamer determination, complementary in silico aptamer design is highly sought after to facilitate virtual screening and increased understanding of important nucleic acid-protein interactions. Here, with a combined experimental and theoretical approach, we have developed two optimal epithelial cellular adhesion molecule (EpCAM) aptamers. Our structure-based in silico method first predicts their binding modes and then optimizes them for EpCAM with molecular dynamics simulations, docking, and free energy calculations. Our isothermal titration calorimetry experiments further confirm that the EpCAM aptamers indeed exhibit enhanced affinity over a previously patented nanomolar aptamer, EP23. Moreover, our study suggests that EP23 and the de novo designed aptamers primarily bind to EpCAM dimers (and not monomers, as hypothesized in previous published works), suggesting a paradigm for developing EpCAM-targeted therapies.
aptamer, systematic evolution of ligands by exponential enrichment, in silico, virtual screening, rational design, isothermal titration calorimetry, docking, nucleic acid, computational biology, chemistry
Rare Dissipative Transitions Punctuate the Initiation of Chemical Denaturation in Proteins
Jeffrey K. Weber, Seung-gu Kang, Ruhong Zhou
Biophysical Journal 114(4), 812-821, 2018
Abstract dissipative system, protein folding, entropy production, denaturation, molecular dynamics, non equilibrium thermodynamics, protein structure, protein domain, chemical physics, chemistry
Abstract 1 Protein unfolding dynamics are bound by their degree of entropy production, a quantity that relates the amount of heat dissipated by a nonequilibrium process to a systems forward and time-reversed trajectories. We here explore the statistics of heat dissipation that emerge in protein molecules subjected to a chemical denaturant. Coupling large molecular dynamics datasets and Markov state models with the theory of entropy production, we demonstrate that dissipative processes can be rigorously characterized over the course of the urea-induced unfolding of the protein chymotrypsin inhibitor 2. By enumerating full entropy production probability distributions as a function of time, we first illustrate that distinct passive and dissipative regimes are present in the denaturation dynamics. Within the dissipative dynamical region, we next find that chymotrypsin inhibitor 2 is strongly driven into unfolded states in which the proteins hydrophobic core has been penetrated by urea molecules and disintegrated. Detailed analyses reveal that ureas interruption of key hydrophobic contacts between core residues causes many of the proteins native structural features to dissolve.
dissipative system, protein folding, entropy production, denaturation, molecular dynamics, non equilibrium thermodynamics, protein structure, protein domain, chemical physics, chemistry
Molecular mechanism of Gd@C82(OH)22 increasing collagen expression: Implication for encaging tumor
Jing Liu, Seung gu Kang, Peng Wang, Yue Wang, Xiaonan Lv, Ying Liu, Fei Wang, Zonglin Gu, Zaixing Yang, Jeffrey K. Weber, Ning Tao, Zhihai Qin, Qing Miao, Chunying Chen, Ruhong Zhou, Yuliang Zhao
Biomaterials152, 24-36, 2018
Abstract cancer cell, tumor necrosis factor alpha, metastasis, receptor, fibrosarcoma, fibroblast, cancer, cancer research, lung cancer, immunology, biology
Abstract 1 2 Gadolinium-containing fullerenol Gd@C 82 (OH) 22 9 has demonstrated low-toxicity and highly therapeutic efficacy in inhibiting tumor growth and metastasis through new strategy of encaging cancer, however, little is known about the mechanisms how this nanoparticle regulates fibroblast cells to prison (instead of poison) cancer cells. Here, we report that Gd@C 82 (OH) 22 57 promote the binding activity of tumor necrosis factor (TNF) to tumor necrosis factor receptors 2 (TNFR2), activate TNFR2/p38 MAPK signaling pathway to increase cellular collagen expression in fibrosarcoma cells and human primary lung cancer associated fibroblasts isolated from patients. We also employ molecular dynamics simulations to study the atomic-scale mechanisms that dictate how Gd@C 82 (OH) 22 115 mediates interactions between TNF and TNFRs. Our data suggest that Gd@C 82 (OH) 22 130 might enhance the association between TNF and TNFR2 through a "bridge-like" mode of interaction; by contrast, the fullerenol appears to inhibit TNF-TNFR1 association by binding to two of the receptors cysteine-rich domains. In concert, our results uncover a sequential, systemic process by which Gd@C 82 (OH) 22 178 acts to prison tumor cells, providing new insights into principles of designs of cancer therapeutics.
cancer cell, tumor necrosis factor alpha, metastasis, receptor, fibrosarcoma, fibroblast, cancer, cancer research, lung cancer, immunology, biology
T cell receptors for the HIV KK10 epitope from patients with differential immunologic control are functionally indistinguishable
Alok V. Joglekar, Zhe Liu, Jeffrey K. Weber, Yong Ouyang, John D. Jeppson, Won Jun Noh, Pedro A. Lamothe-Molina, Huabiao Chen, Seung-gu Kang, Michael T. Bethune, Ruhong Zhou, Bruce D. Walker, David Baltimore
Proceedings of the National Academy of Sciences of the United States of America 115(8), 1877-1882, 2018
Abstract t cell, natural killer t cell, epitope, cd8, cytokine secretion, t cell receptor, cytotoxicity, in vitro, molecular biology, chemistry
HIV controllers (HCs) are individuals who can naturally control HIV infection, partially due to potent HIV-specific CD8+ T cell responses. Here, we examined the hypothesis that superior function of CD8+ T cells from HCs is encoded by their T cell receptors (TCRs). We compared the functional properties of immunodominant HIV-specific TCRs obtained from HLA-B*2705 HCs and chronic progressors (CPs) following expression in primary T cells. T cells transduced with TCRs from HCs and CPs showed equivalent induction of epitope-specific cytotoxicity, cytokine secretion, and antigen-binding properties. Transduced T cells comparably, albeit modestly, also suppressed HIV infection in vitro and in humanized mice. We also performed extensive molecular dynamics simulations that provided a structural basis for similarities in cytotoxicity and epitope cross-reactivity. These results demonstrate that the differential abilities of HIV-specific CD8+ T cells from HCs and CPs are not genetically encoded in the TCRs alone and must depend on additional factors.
t cell, natural killer t cell, epitope, cd8, cytokine secretion, t cell receptor, cytotoxicity, in vitro, molecular biology, chemistry
Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy
Diego Chowell, Luc G. T. Morris, Claud M. Grigg, Jeffrey K. Weber, Robert M. Samstein, Vladimir Makarov, Fengshen Kuo, Sviatoslav M. Kendall, David Requena, Nadeem Riaz, Benjamin Greenbaum, James Carroll, Edward Garon, David M. Hyman, Ahmet Zehir, David Solit, Michael Berger, Ruhong Zhou, Naiyer A. Rizvi, Timothy A. Chan
Science 359(6375), 582-587, 2018
Abstract checkpoint blockade immunotherapy, immune checkpoint, human leukocyte antigen, t cell, antigen, cd8, loss of heterozygosity, cancer, immunology, medicine
CD8 + 2 T cell-dependent killing of cancer cells requires efficient presentation of tumor antigens by human leukocyte antigen class I (HLA-I) molecules. However, the extent to which patient-specific HLA-I genotype influences response to anti-programmed cell death protein 1 or anti-cytotoxic T lymphocyte-associated protein 4 is currently unknown. We determined the HLA-I genotype of 1535 advanced cancer patients treated with immune checkpoint blockade (ICB). Maximal heterozygosity at HLA-I loci ("A," "B," and "C") improved overall survival after ICB compared with patients who were homozygous for at least one HLA locus. In two independent melanoma cohorts, patients with the HLA-B44 supertype had extended survival, whereas the HLA-B62 supertype (including HLA-B*15:01) or somatic loss of heterozygosity at HLA-I was associated with poor outcome. Molecular dynamics simulations of HLA-B*15:01 revealed different elements that may impair CD8 + 134 T cell recognition of neoantigens. Our results have important implications for predicting response to ICB and for the design of neoantigen-based therapeutic vaccines.
checkpoint blockade immunotherapy, immune checkpoint, human leukocyte antigen, t cell, antigen, cd8, loss of heterozygosity, cancer, immunology, medicine
Emerging -Sheet Rich Conformations in Supercompact Huntingtin Exon-1 Mutant Structures
Hongsuk Kang, Francisco X. Vazquez, Leili Zhang, Payel Das, Leticia Marisel Toledo-Sherman, Binquan Luan, Michael Levitt, Ruhong Zhou
Journal of the American Chemical Society 139(26), 8820-8827, 2017
Abstract huntingtin protein, huntingtin, beta sheet, protein secondary structure, molecular dynamics, exon, mutant, hydrogen bond, biophysics, crystallography, chemistry
There exists strong correlation between the extended polyglutamines (polyQ) within exon-1 of Huntingtin protein (Htt) and age onset of Huntingtons disease (HD); however, the underlying molecular mechanism is still poorly understood. Here we apply extensive molecular dynamics simulations to study the folding of Htt-exon-1 across five different polyQ-lengths. We find an increase in secondary structure motifs at longer Q-lengths, including -sheet content that seems to contribute to the formation of increasingly compact structures. More strikingly, these longer Q-lengths adopt supercompact structures as evidenced by a surprisingly small power-law scaling exponent (0.22) between the radius-of-gyration and Q-length that is substantially below expected values for compact globule structures (0.33) and unstructured proteins (0.50). Hydrogen bond analyses further revealed that the supercompact behavior of polyQ is mainly due to the "glue-like" behavior of glutamines side chains with significantly more side cha...
huntingtin protein, huntingtin, beta sheet, protein secondary structure, molecular dynamics, exon, mutant, hydrogen bond, biophysics, crystallography, chemistry
Phosphatidylserine-Induced Conformational Modulation of Immune Cell Exhaustion-Associated Receptor TIM3
Jeffrey K Weber, Ruhong Zhou
Scientific Reports 7(1), 13579-13579, 2017
Abstract immune receptor, conformational change, receptor, binding site, protein structure, salt bridge, phosphorylation, small molecule, biophysics, chemistry
In the face of chronic cancers and protracted viral infections, human immune cells are known to adopt an exhausted state in which their effector functions are lost. In recent years, a number of inhibitory receptors have been connected to the immune cell exhaustion phenotype; furthermore, ligands capable of activating these receptors have been discovered. The molecular mechanisms by which these ligands affect the exhausted states of immune cells, however, are largely unknown. Here, we present the results of molecular dynamics simulations of one potential exhaustion-associated system: the complex of human inhibitory receptor TIM3 (hTIM3) and its ligand phosphatidylserine (PSF). We find that PSF fundamentally alters the electrostatic environment within hTIM3s Ca2+ binding site, facilitating the formation of a salt bridge and freeing a tyrosine-containing strand. This liberated tyrosine then collapses into a nearby hydrophobic pocket, anchoring a modified conformational ensemble typified by a -strand rearrangement. The "electrostatic switching/hydrophobic anchoring" mechanism of conformational modulation reported here suggests a new type of process by which TIM3 activation might be achieved. This work also highlights strategies by which PSF-mediated conformational change could be controlled, either through administration of small molecules, execution of mutations, or modification of receptor phosphorylation states.
immune receptor, conformational change, receptor, binding site, protein structure, salt bridge, phosphorylation, small molecule, biophysics, chemistry
Directional mechanical stability of Bacteriophage 29 motors 3WJ-pRNA: Extraordinary robustness along portal axis
Zhonghe Xu, Yang Sun, Jeffrey K. Weber, Yi Cao, Wei Wang, Daniel Jasinski, Peixuan Guo, Ruhong Zhou, Jingyuan Li
Science Advances 3(5), 1-8, 2017
Abstract molecular motor, prohead, force spectroscopy, dna condensation, helix, coaxial, molecular dynamics, rigidity, biophysics, nanotechnology
The molecular motor exploited by bacteriophage 29 to pack DNA into its capsid is regarded as one of the most powerful mechanical devices present in viral, bacterial, and eukaryotic systems alike. Acting as a linker element, a prohead RNA (pRNA) effectively joins the connector and ATPase (adenosine triphosphatase) components of the 29 motor. During DNA packing, this pRNA needs to withstand enormous strain along the capsids portal axishow this remarkable stability is achieved remains to be elucidated. We investigate the mechanical properties of the 29 motors three-way junction (3WJ)-pRNA using a combined steered molecular dynamics and atomic force spectroscopy approach. The 3WJ exhibits strong resistance to stretching along its coaxial helices, demonstrating its super structural robustness. This resistance disappears, however, when external forces are applied to the transverse directions. From a molecular standpoint, we demonstrate that this direction-dependent stability can be attributed to two Mg clamps that cooperate and generate mechanical resistance in the pRNAs coaxial direction. Our results suggest that the asymmetric nature of the 3WJs mechanical stability is entwined with its biological function: Enhanced rigidity along the portal axis is likely essential to withstand the strain caused by DNA condensation, and flexibility in other directions should aid in the assembly of the pRNA and its association with other motor components.
molecular motor, prohead, force spectroscopy, dna condensation, helix, coaxial, molecular dynamics, rigidity, biophysics, nanotechnology
Graphene-Induced Pore Formation on Cell Membranes
Guangxin Duan, Yuanzhao Zhang, Binquan Luan, Jeffrey K. Weber, Royce W. Zhou, Zaixing Yang, Lin Zhao, Jiaying Xu, Judong Luo, Ruhong Zhou
Scientific Reports 7(1), 2017
Abstract membrane, bilayer, graphene, nanomaterials, viability assay, molecular dynamics, cytotoxicity, biophysics, cell, chemistry
Examining interactions between nanomaterials and cell membranes can expose underlying mechanisms of nanomaterial cytotoxicity and guide the design of safer nanomedical technologies. Recently, graphene has been shown to exhibit potential toxicity to cells; however, the molecular processes driving its lethal properties have yet to be fully characterized. We here demonstrate that graphene nanosheets (both pristine and oxidized) can produce holes (pores) in the membranes of A549 and Raw264.7 cells, substantially reducing cell viability. Electron micrographs offer clear evidence of pores created on cell membranes. Our molecular dynamics simulations reveal that multiple graphene nanosheets can cooperate to extract large numbers of phospholipids from the membrane bilayer. Strong dispersion interactions between graphene and lipid-tail carbons result in greatly depleted lipid density within confined regions of the membrane, ultimately leading to the formation of water-permeable pores. This cooperative lipid extraction mechanism for membrane perforation represents another distinct process that contributes to the molecular basis of graphene cytotoxicity.
membrane, bilayer, graphene, nanomaterials, viability assay, molecular dynamics, cytotoxicity, biophysics, cell, chemistry
PEGylated graphene oxide elicits strong immunological responses despite surface passivation
Nana Luo, Jeffrey K. Weber, Shuang Wang, Binquan Luan, Hua Yue, Xiaobo Xi, Jing Du, Zaixing Yang, Wei Wei, Ruhong Zhou, Guanghui Ma
Nature Communications 8(1), 14537-14537, 2017
Abstract cytokine secretion, nanomaterials, signal transduction, integrin, cytokine, cell membrane, immune system, membrane, biophysics, nanotechnology, chemistry
Engineered nanomaterials promise to transform medicine at the bio-nano interface. However, it is important to elucidate how synthetic nanomaterials interact with critical biological systems before such products can be safely utilized in humans. Past evidence suggests that polyethylene glycol-functionalized (PEGylated) nanomaterials are largely biocompatible and elicit less dramatic immune responses than their pristine counterparts. We here report results that contradict these findings. We find that PEGylated graphene oxide nanosheets (nGO-PEGs) stimulate potent cytokine responses in peritoneal macrophages, despite not being internalized. Atomistic molecular dynamics simulations support a mechanism by which nGO-PEGs preferentially adsorb onto and/or partially insert into cell membranes, thereby amplifying interactions with stimulatory surface receptors. Further experiments demonstrate that nGO-PEG indeed provokes cytokine secretion by enhancing integrin 8-related signalling pathways. The present results inform that surface passivation does not always prevent immunological reactions to 2D nanomaterials but also suggest applications for PEGylated nanomaterials wherein immune stimulation is desired.
cytokine secretion, nanomaterials, signal transduction, integrin, cytokine, cell membrane, immune system, membrane, biophysics, nanotechnology, chemistry
Particle Size-Dependent Antibacterial Activity and Murine Cell Cytotoxicity Induced by Graphene Oxide Nanomaterials
Lin Zhao, Guangxin Duan, Zaixing Yang, Jeffrey K. Weber, Xu Liu, Shunyi Lu, Xuanyu Meng, JiaYing Xu
Journal of Nanomaterials2016
Abstract antibacterial activity, graphene, cytotoxicity, nanomaterials, nanoparticle, particle size, biophysics, cytotoxic t cell, quantum dot, chemistry, nanotechnology
Recent studies have indicated that graphene and its derivative graphene oxide (GO) engage in a wide range of antibacterial activities with limited toxicity to human cells. Here, we systematically evaluate the dependence of GO toxicity on the size of the nanoparticles used in treatments: we compare the cytotoxic effects of graphene quantum dots (GQDs, <15znm), small GOs (SGOs, 50z200znm), and large GOs (LGOs, 0.5z3zzm). We synthesize the results of bacterial colony count assays and SEM-based observations of morphological changes to assess the antibacterial properties that these GOs bring into effect against E. coli. We also use Live/Dead assays and morphological analysis to investigate changes to mammalian (Murine macrophage-like Raw 264.7) cells induced by the presence of the various GO particle types. Our results demonstrate that LGOs, SGOs, and GQDs possess antibacterial activities and cause mammalian cell cytotoxicity at descending levels of potency. Placing our observations in the context of previous simulation results, we suggest that both the lateral size and surface area of GO particles contribute to cytotoxic effects. We hope that the size dependence elucidated here provides a useful schematic for tuning GO-cell interactions in biomedical applications.
antibacterial activity, graphene, cytotoxicity, nanomaterials, nanoparticle, particle size, biophysics, cytotoxic t cell, quantum dot, chemistry, nanotechnology
Sequential protein unfolding through a carbon nanotube pore
Xu, Zhonghe and Zhang, Shuang and Weber, Jeffrey K and Luan, Binquan and Zhou, Ruhong and Li, Jingyuan
Nanoscale, Royal Society of Chemistry, 2016
An assortment of biological processes, like protein degradation and the transport of proteins across membranes, depend on protein unfolding events mediated by nanopore interfaces. In this work, we exploit fully atomistic simulations of an artificial, CNT-based nanopore to
Single-Walled Carbon Nanotubes Inhibit the Cytochrome P450 Enzyme, CYP3A4
Ramy El-Sayed, Kunal Bhattacharya, Zhonglin Gu, Zaixing Yang, Jeffrey K. Weber, Hu Li, Klaus Leifer, Yichen Zhao, Muhammet S. Toprak, Ruhong Zhou, Bengt Fadeel
Scientific Reports 6(1), 21316-21316, 2016
Abstract cytochrome p 450 cyp3a, enzyme assay, bovine serum albumin, cytochrome p 450 cyp3a inhibitors, polyethylene glycol, metabolite, enzyme, cyp3a4, biophysics, chemistry, biochemistry
We report a detailed computational and experimental study of the interaction of single-walled carbon nanotubes (SWCNTs) with the drug-metabolizing cytochrome P450 enzyme, CYP3A4. Dose-dependent inhibition of CYP3A4-mediated conversion of the model compound, testosterone, to its major metabolite, 6-hydroxy testosterone was noted. Evidence for a direct interaction between SWCNTs and CYP3A4 was also provided. The inhibition of enzyme activity was alleviated when SWCNTs were pre-coated with bovine serum albumin. Furthermore, covalent functionalization of SWCNTs with polyethylene glycol (PEG) chains mitigated the inhibition of CYP3A4 enzymatic activity. Molecular dynamics simulations suggested that inhibition of the catalytic activity of CYP3A4 is mainly due to blocking of the exit channel for substrates/products through a complex binding mechanism. This work suggests that SWCNTs could interfere with metabolism of drugs and other xenobiotics and provides a molecular mechanism for this toxicity. Our study also suggests means to reduce this toxicity, eg., by surface modification.
cytochrome p 450 cyp3a, enzyme assay, bovine serum albumin, cytochrome p 450 cyp3a inhibitors, polyethylene glycol, metabolite, enzyme, cyp3a4, biophysics, chemistry, biochemistry
Folding and Stabilization of Native-Sequence-Reversed Proteins
Yuanzhao Zhang, Jeffrey K Weber, Ruhong Zhou
Scientific Reports 6(1), 25138-25138, 2016
Abstract protein design, protein structure, protein structure prediction, protein folding, amino acid, molecular dynamics, computational biology, chemistry, native protein, protein size
Though the problem of sequence-reversed protein folding is largely unexplored, one might speculate that reversed native protein sequences should be significantly more foldable than purely random heteropolymer sequences. In this article, we investigate how the reverse-sequences of native proteins might fold by examining a series of small proteins of increasing structural complexity (-helix, -hairpin, -helix bundle, and /-protein). Employing a tandem protein structure prediction algorithmic and molecular dynamics simulation approach, we find that the ability of reverse sequences to adopt native-like folds is strongly influenced by protein size and the flexibility of the native hydrophobic core. For -hairpins with reverse-sequences that fail to fold, we employ a simple mutational strategy for guiding stable hairpin formation that involves the insertion of amino acids into the -turn region. This systematic look at reverse sequence duality sheds new light on the problem of protein sequence-structure mapping and may serve to inspire new protein design and protein structure prediction protocols.
protein design, protein structure, protein structure prediction, protein folding, amino acid, molecular dynamics, computational biology, chemistry, native protein, protein size
Tunable, Strain-Controlled Nanoporous MoS2 Filter for Water Desalination
Weifeng Li, Yanmei Yang, Jeffrey K. Weber, Gang Zhang, Ruhong Zhou
ACS Nano 10(2), 1829-1835, 2016
Abstract desalination, nanoporous, nanosheet, nanopore, seawater, graphene, nanotechnology, materials science, fresh water, water desalination
The deteriorating state of global fresh water resources represents one of the most serious challenges that scientists and policymakers currently face. Desalination technologies, which are designed to extract potable water from the planets bountiful stores of seawater, could serve to alleviate much of the stress that presently plagues fresh water supplies. In recent decades, desalination methods have improved via water-filtering architectures based on nanoporous graphene filters and artificial membranes integrated with biological water channels. Here, we report the auspicious performance (in simulations) of an alternative nanoporous desalination filter constructed from a MoS2 nanosheet. In striking contrast to graphene-based filters, we find that the "open" and "closed" states of the MoS2 filter can be regulated by the introduction of mechanical strain, yielding a highly tunable nanopore interface. By applying lateral strain to the MoS2 filter in our simulations, we see that the transition point between "...
desalination, nanoporous, nanosheet, nanopore, seawater, graphene, nanotechnology, materials science, fresh water, water desalination
A novel form of -strand assembly observed in A(33-42) adsorbed onto graphene
Xiaofeng Wang, Jeffrey K. Weber, Lei Liu, Mingdong Dong, Ruhong Zhou, Jingyuan Li
Nanoscale 7(37), 15341-15348, 2015
Abstract hydrophobic effect, antiparallel, peptide, hydrogen bond, molecule, molecular dynamics, graphene, biophysics, adsorption, combinatorial chemistry, chemistry
Peptide assembly plays a seminal role in the fabrication of structural and functional architectures in cells. Characteristically, peptide assemblies are often dominated by beta-sheet structures, wherein component molecules are connected by backbone hydrogen bonds in a parallel or an antiparallel fashion. While beta-rich peptide scaffolds are implicated in an array of neurodegenerative diseases, the mechanisms by which toxic peptides assemble and mediate neuropathic effects are still poorly understood. In this work, we employ molecular dynamics simulations to study the adsorption and assembly of the fragment A beta(33-42) (taken from the A beta-42 peptide widely associated with Alzheimers disease) on a graphene surface. We observe that such A beta(33-42) fragments, which are largely hydrophobic in character, readily adsorb onto the graphitic surface and coalesce into a well-structured, beta-strand-like assembly. Strikingly, the structure of such complex is quite unique: hydrophobic side-chains extend over the graphene surface and interact with adjacent peptides, yielding a well-defined mosaic of hydrophobic interaction patches. This ordered structure is markedly depleted of backbone hydrogen bonds. Hence, our simulation results reveal a distinct type of beta-strand assembly, maintained by hydrophobic side-chain interactions. Our finding suggests the backbone hydrogen bond is no longer crucial to the peptide assembly. Further studies concerning whether such beta-strand assembly can be realized in other peptide systems and in biologically-relevant contexts are certainly warranted.
hydrophobic effect, antiparallel, peptide, hydrogen bond, molecule, molecular dynamics, graphene, biophysics, adsorption, combinatorial chemistry, chemistry
Surface curvature relation to protein adsorption for carbon-based nanomaterials
Gu, Zonglin and Yang, Zaixing and Chong, Yu and Ge, Cuicui and Weber, Jeffrey K and Bell, David R and Zhou, Ruhong
Scientific reports5, 10886, Nature Publishing Group, 2015
The adsorption of proteins onto carbon-based nanomaterials (CBNs) is dictated by hydrophobic and Ï€-Ï€ interactions between aliphatic and aromatic residues and the conjugated CBN surface. Accordingly, protein adsorption is highly sensitive to topological constraints imposed by CBN surface structure; in particular, adsorption capacity is thought to increase as the incident surface curvature decreases. In this work, we couple Molecular Dynamics (MD) simulations with fluorescence spectroscopy experiments to characterize this â€¦
A Peptide-Coated Gold Nanocluster Exhibits Unique Behavior in Protein Activity Inhibition
Deyi An, Jiguo Su, Jeffrey K. Weber, Xueyun Gao, Ruhong Zhou, Jingyuan Li
Journal of the American Chemical Society 137(26), 8412-8418, 2015
Abstract peptide, protein structure, nanoclusters, active site, static electricity, nanoparticle, surface modification, coating, biophysics, chemistry, nanotechnology
Gold nanoclusters (AuNCs) can be primed for biomedical applications through functionalization with peptide coatings. Often anchored by thiol groups, such peptide coronae not only serve as passivators but can also endow AuNCs with additional bioactive properties. In this work, we use molecular dynamics simulations to study the structure of a tridecapeptide-coated Au25 cluster and its subsequent interactions with the enzyme thioredoxin reductase 1, TrxR1. We find that, in isolation, both the distribution and conformation of the coating peptides fluctuate considerably. When the coated AuNC is placed around TrxR1, however, the motion of the highly charged peptide coating (+5e/peptide) is quickly biased by electrostatic attraction to the protein; the asymmetric coating acts to guide the nanoclusters diffusion toward the enzymes negatively charged active site. After the AuNC comes into contact with TrxR1, its peptide corona spreads over the protein surface to facilitate stable binding with protein. Though ind...
peptide, protein structure, nanoclusters, active site, static electricity, nanoparticle, surface modification, coating, biophysics, chemistry, nanotechnology