De novo discovery of peptide-based affinity ligands for the fab fragment of human immunoglobulin G
}, volume={1669}, ISSN={["1873-3778"]}, DOI={10.1016/j.chroma.2022.462941}, abstractNote={Antibody fragments and their engineered variants show true potential as next-generation therapeutics as they combine excellent targeting with superior biodistribution and blood clearance. Unlike full antibodies, however, antibody fragments do not yet have a standard platform purification process for large-scale production. Short peptide ligands are viable alternatives to protein ligands in affinity chromatography. In this work, an integrated computational and experimental scheme is described to de novo design 9-mer peptides that bind to Fab fragments. The first cohort of designed sequences was tested experimentally using human polyclonal Fab, and the top performing sequence was selected as a prototype for a subsequent round of ligand refinement in silico. The resulting peptides were conjugated to chromatographic resins and evaluated via equilibrium and dynamic binding studies using human Fab-κ and Fab-λ. The equilibrium studies returned values of binding capacities up to 32 mg of Fab per mL of resin with mild affinity (KD ∼ 10-5 M) that are conducive to high product capture and recovery. Dynamic studies returned values of product yield up to ∼90%. Preliminary purification studies provided purities of 83-93% and yields of 11-89%. These results lay the groundwork for future development of these ligands towards biomanufacturing translation.}, journal={JOURNAL OF CHROMATOGRAPHY A}, author={Xiao, Xingqing and Kilgore, Ryan and Sarma, Sudeep and Chu, Wenning and Menegatti, Stefano and Hall, Carol K.}, year={2022}, month={Apr} } @article{sarma_herrera_xiao_hudalla_hall_2022, title={Computational Design and Experimental Validation of ACE2-Derived Peptides as SARS-CoV-2 Receptor Binding Domain Inhibitors}, volume={126}, ISSN={["1520-5207"]}, DOI={10.1021/acs.jpcb.2c039188129J}, number={41}, journal={JOURNAL OF PHYSICAL CHEMISTRY B}, author={Sarma, Sudeep and Herrera, Stephanie M. and Xiao, Xingqing and Hudalla, Gregory A. and Hall, Carol K.}, year={2022}, month={Oct}, pages={8129–8139} } @article{xiao_robang_sarma_le_helmicki_lambert_guerrero-ferreira_arboleda-echavarria_paravastu_hall_2022, title={Sequence patterns and signatures: Computational and experimental discovery of amyloid-forming peptides}, volume={1}, ISSN={["2752-6542"]}, DOI={10.1093/pnasnexus/pgac263}, abstractNote={Abstract}, number={5}, journal={PNAS NEXUS}, author={Xiao, Xingqing and Robang, Alicia S. and Sarma, Sudeep and Le, Justin V. and Helmicki, Michael E. and Lambert, Matthew J. and Guerrero-Ferreira, Ricardo and Arboleda-Echavarria, Johana and Paravastu, Anant K. and Hall, Carol K.}, year={2022}, month={Nov} } @article{xiao_wang_seroski_wong_liu_paravastu_hudalla_hall_2021, title={De novo design of peptides that coassemble into beta sheet-based nanofibrils}, volume={7}, ISSN={["2375-2548"]}, DOI={10.1126/sciadv.abf7668}, abstractNote={Computational discoveries and experimental characterizations of coassembly peptides that form β sheet–based nanofibrils.}, number={36}, journal={SCIENCE ADVANCES}, author={Xiao, Xingqing and Wang, Yiming and Seroski, Dillon T. and Wong, Kong M. and Liu, Renjie and Paravastu, Anant K. and Hudalla, Gregory A. and Hall, Carol K.}, year={2021}, month={Sep} } @article{wong_robang_lint_wang_dong_xiao_seroski_liu_shao_hudalla_et al._2021, title={Engineering beta-Sheet Peptide Coassemblies for Biomaterial Applications}, volume={12}, ISSN={["1520-5207"]}, DOI={10.1021/acs.jpcb.1c04873}, abstractNote={Peptide coassembly, wherein at least two different peptides interact to form multicomponent nanostructures, is an attractive approach for generating functional biomaterials. Current efforts seek to design pairs of peptides, A and B, that form nanostructures (e.g., β-sheets with ABABA-type β-strand patterning) while resisting self-assembly (e.g., AAAAA-type or BBBBB-type β-sheets). To confer coassembly behavior, most existing designs have been based on highly charged variants of known self-assembling peptides; like-charge repulsion limits self-assembly while opposite-charge attraction promotes coassembly. Recent analyses using solid-state NMR and coarse-grained simulations reveal that preconceived notions of structure and molecular organization are not always correct. This perspective highlights recent advances and key challenges to understanding and controlling peptide coassembly.}, journal={JOURNAL OF PHYSICAL CHEMISTRY B}, author={Wong, Kong M. and Robang, Alicia S. and Lint, Annabelle H. and Wang, Yiming and Dong, Xin and Xiao, Xingqing and Seroski, Dillon T. and Liu, Renjie and Shao, Qing and Hudalla, Gregory A. and et al.}, year={2021}, month={Dec} } @article{xiao_sarma_menegatti_crook_magness_hall_2021, title={In Silico Identification and Experimental Validation of Peptide-Based Inhibitors Targeting Clostridium difficile Toxin A}, volume={17}, ISSN={["1554-8937"]}, url={https://doi.org/10.1021/acschembio.1c00743}, DOI={10.1021/acschembio.1c00743}, abstractNote={Clostridium difficile infection is mediated by two major exotoxins: toxins A (TcdA) and B (TcdB). Inhibiting the biocatalytic activities of these toxins with targeted peptide-based drugs can reduce the risk of C. difficile infection. In this work, we used a computational strategy that integrates a peptide binding design (PepBD) algorithm and explicit-solvent atomistic molecular dynamics simulation to determine promising toxin A-targeting peptides that can recognize and bind to the catalytic site of the TcdA glucosyltransferase domain (GTD). Our simulation results revealed that two out of three in silico discovered peptides, viz. the neutralizing peptides A (NPA) and B (NPB), exhibit lower binding free energies when bound to the TcdA GTD than the phage-display discovered peptide, viz. the reference peptide (RP). These peptides may serve as potential inhibitors against C. difficile infection. The efficacy of the peptides RP, NPA, and NPB to neutralize the cytopathic effects of TcdA was tested in vitro in human jejunum cells. Both phage-display peptide RP and in silico peptide NPA were found to exhibit strong toxin-neutralizing properties, thereby preventing the TcdA toxicity. However, the in silico peptide NPB demonstrates a relatively low efficacy against TcdA.}, number={1}, journal={ACS CHEMICAL BIOLOGY}, publisher={American Chemical Society (ACS)}, author={Xiao, Xingqing and Sarma, Sudeep and Menegatti, Stefano and Crook, Nathan and Magness, Scott T. and Hall, Carol K.}, year={2021}, month={Dec} } @article{xiao_kuang_burke_chushak_farmer_mirau_naik_hall_2020, title={In Silico Discovery and Validation of Neuropeptide-Y-Binding Peptides for Sensors}, volume={124}, ISSN={["1520-5207"]}, DOI={10.1021/acs.jpcb.9b09439}, abstractNote={Wearable sensors for human health, performance and state monitoring which have a linear response to the binding of biomarkers found in sweat, saliva or urine are of current interest for many applications. A critical part of any device is a biological recognition element (BRE) that is able to bind a biomarker at the surface of a sensor with a high affinity and selectivity to produce a measurable signal response. In this study, we discover and compare 12-mer peptides that bind to neuropeptide Y (NPY), a stress and human health biomarker, using independent and complimentary experi-mental and computational approaches. The affinities of the NPY-binding peptides discovered by both methods are equivalent and below the μM level, which makes them suitable for application in sensors. The in-silico design protocol for peptide-based BREs is low cost, highly efficient, and simple, suggesting its utility for discovering peptide binders to a variety of biomarker targets.}, number={1}, journal={JOURNAL OF PHYSICAL CHEMISTRY B}, author={Xiao, Xingqing and Kuang, Zhifeng and Burke, B. J. and Chushak, Yaroslav and Farmer, Barry L. and Mirau, Peter A. and Naik, Rajesh R. and Hall, Carol K.}, year={2020}, month={Jan}, pages={61–68} } @article{reese_xiao_shanahan_driessche_fourches_carbonell_hall_menegatti_2020, title={Novel peptide ligands for antibody purification provide superior clearance of host cell protein impurities}, volume={1625}, ISSN={["1873-3778"]}, DOI={10.1016/j.chroma.2020.461237}, abstractNote={The quest for ligands alternative to Protein A for the purification of monoclonal antibodies (mAbs) has been pursued for almost three decades. Yet, the IgG-binding peptides known to date still fall short of the host cell protein (HCP) logarithmic removal value (LRV) set by Protein A media (2.5-3.1). In this study, we present an integrated computational-experimental approach leading to the discovery of peptide ligands that provide HCP LRVs on par with Protein A. First, the screening of 60,000 peptide variants was performed using a high-throughput search algorithm to identify sequences that ensure IgG affinity binding. Select sequences WQRHGI, MWRGWQ, RHLGWF, and GWLHQR were then negatively screened in silico against a panel of model HCPs to ensure the selection of peptides with high binding selectivity. Candidate ligands WQRHGI and MWRGWQ were conjugated to chromatographic resins and characterized by isothermal binding and breakthrough assays to quantify static and dynamic binding capacity (Qmax and DBC10%), respectively. The resulting Qmax were 52.6 mg of IgG per mL of adsorbent for WQRHGI and 57.48 mg/mL for MWRGWQ, while the DBC10% (2 minutes residence time) were 30.1 mg/mL for WQRHGI and 36.4 mg/mL for MWRGWQ. Evaluation of the peptides by isothermal titration calorimetry (ITC) confirmed the binding energy predicted in silico, and an amino acid scanning study corroborated the affinity-like binding activity of the peptides. WQRHGI-WorkBeads resin was finally characterized by purification of a monoclonal antibody from a Chinese Hamster Ovary (CHO) cell culture harvest, affording a remarkable HCP LRV of 2.7, and consistent product yield and purity over 100 chromatographic cycles. These results demonstrate the potential of WQRHGI as an effective alternative to Protein A for antibody purification.}, journal={JOURNAL OF CHROMATOGRAPHY A}, author={Reese, Hannah R. and Xiao, Xingqing and Shanahan, Calvin C. and Driessche, George A. and Fourches, Denis and Carbonell, Ruben G. and Hall, Carol K. and Menegatti, Stefano}, year={2020}, month={Aug} } @article{yan_tang_zhou_yang_xiao_chen_qin_sun_2019, title={All-silica zeolites screening for capture of toxic gases from molecular simulation}, volume={27}, ISSN={["2210-321X"]}, DOI={10.1016/j.cjche.2018.02.025}, abstractNote={The exhaust gases, including SO2, NH3, H2S, NO2, NO, and CO, are principal air pollutants due to their severe harms to the ecological environment. Zeolites have been considered as good absorbent candidates to capture the six exhaust gases. In this work, we performed grand canonical ensemble Monte Carlo (GCMC) simulations to examine the capability of 95 kinds of all-silica zeolites in the removal of the six toxic gases, and to predict the adsorption isotherms of the six gases on all the zeolites. The simulation results showed that, H2S, NO, NO2, CO and NH3 are well-captured by zeolite structures with accessible surface area of 1600–1800 m2·g− 1 and pore diameter of 0.6–0.7 nm, such as AFY and PAU, while SO2 is well-adsorbed by zeolites containing larger accessible surface area (1700–2700 m2·g− 1) and pore diameter (0.7–1.4 nm) at room temperature and an atmospheric pressure. However, at saturated adsorption, zeolites RWY, IRR, JSR, TSC, and ITT are found to exhibit better abilities to capture these gases. Our study provides useful computational insights in choosing and designing zeolite structures with high performance to remove toxic gases for air purification, thereby facilitating the development and application of exhaust gas-processing technology in green industry.}, number={1}, journal={CHINESE JOURNAL OF CHEMICAL ENGINEERING}, author={Yan, Zhiguo and Tang, Sai and Zhou, Xumiao and Yang, Li and Xiao, Xingqing and Chen, Houyang and Qin, Yuanhang and Sun, Wei}, year={2019}, month={Jan}, pages={174–181} } @article{xiejun_xingqing_shouhong_hongai_2019, title={Computational Study of Thermosensitivity of Liposomes Modulated by Leucine Zipper-Structured Lipopeptides}, volume={35}, ISSN={["1000-6818"]}, DOI={10.3866/PKU.WHXB201806034}, abstractNote={: Leucine zipper-functionalized liposomes are promising drug carriers for cancer treatment because of their unique thermosensitivity. The leucine zippers, which consist of two α -helical polypeptides that dimerize in parallel, have characteristic heptad repeats (represented by [abcdefg] n ). A leucine residue was observed periodically at site “d” to stabilize the dimerization of the two polypeptides through inter-chain hydrophobic interactions. As the temperature increased, the inter-chain hydrophobic interactions became weaker, eventually triggering the dissociation of the leucine zippers. Due to the unique nature of the temperature response, leucine zippers are useful for developing novel lipid-peptide vesicles for drug delivery because they allow for better control and optimization of drug release under mild hyperthermia. The base sequence of the leucine zipper peptides used in our lab for the functionalize liposomal carrier is [VAQLEVK-VAQLESK-VSKLESK-VSSLESK]. Our recent experiments revealed that modifying this peptide at the N-terminus with distinct functional groups can change the physicochemical properties of the lipopeptides, and eventually affect the liposomes’ phase transition behaviors. Four leucine zipper-structured lipopeptides with distinct head groups, viz . ALA, C3CO, C5CO, and POCH, were studied computationally to examine the influence of the molecular structures on the phase transition behaviors of lipopeptides. A series of computational techniques including quantum mechanics (QM) calculations, implicit solvation replica exchange molecular dynamics (REMD) simulations, dihedral principal component analysis (dPCA), and dictionary of protein secondary structure (DSSP) methods, and the conventional explicit solvation molecular dynamics (MD) simulations were applied in this work. First, QM calculations were conducted to obtain the partial charges of some modified head groups. Implicit-solvent REMD simulations were then performed to study the effect of temperature on the folded conformations of the leucine zipper peptides. The dPCA method was used to simulate trajectories to identify representative structures of the peptides at various temperatures, and the DSSP method was used to determine conformation transitions of the four lipopeptides ALA, C3CO, C5CO, and POCH at 324.8, 312.1, 319.1, and 319.4 K, respectively. The thermostability of the lipopeptide dimers in the lipid DPPC bilayer was studied in the conventional explicit solvent MD simulations. Finally, we conducted a deep analysis on the area per lipid and the electron-density profile for the DPPC bilayer to explore the folding and unfolding processes of the lipopeptides in the liposomes to better understand the underlying phase transition mechanisms of the thermosensitive liposomes. On this basis, we could further improve the thermosensitivity of the leucine zipper-structured lipopeptides, thereby facilitating the development of liposomal drug delivery techniques in the future.}, number={6}, journal={ACTA PHYSICO-CHIMICA SINICA}, author={Xiejun, Xu and Xingqing, Xiao and Shouhong, Xu and Hongai, Liu}, year={2019}, pages={598–606} } @article{li_chen_xiao_yang_peng_qin_wang_sun_wang_2019, title={Computational study of transition states for reaction path of energetic material TKX-50}, volume={37}, ISSN={["1545-8822"]}, DOI={10.1080/07370652.2019.1590482}, abstractNote={ABSTRACT Dihydroxylammonium5,5′-bistetrazole-1,1′-diolate (TKX-50) is considered as one of the new ionic energetic materials. In this study, we employed density functional theory (DFT) method to calculate the reaction path of TKX-50 and search its optimized configurations of reactants, reactant complexes (RCs), transition states (TSs), product complexes (PCs), and products. We proposed 10 simple reactions in the reaction path, and determined their transition states. Among these TSs, six of them have lower energies than those of reactants. The equilibrium constants, which indicate the limitation of reactions, were computed from the difference of Gibbs free energy with temperature change. Based on the proposed reaction path, the reaction mechanism of TKX-50 was provided.}, number={2}, journal={JOURNAL OF ENERGETIC MATERIALS}, author={Li, Miao and Chen, Houyang and Xiao, Xingqing and Yang, Li and Peng, Changjun and Qin, Yuanhang and Wang, Tielin and Sun, Wei and Wang, Cunwen}, year={2019}, month={Apr}, pages={240–250} } @article{tong_xiao_liang_solms_huo_he_zhang_2019, title={Insights into the solvation and dynamic behaviors of a lithium salt in organic- and ionic liquid-based electrolytes}, volume={21}, ISSN={["1463-9084"]}, DOI={10.1039/c9cp01848d}, abstractNote={Fundamental molecular insights were provided to understand the advantages of IL solvent electrolytes with high conductivity over organic solvent electrolytes.}, number={35}, journal={PHYSICAL CHEMISTRY CHEMICAL PHYSICS}, author={Tong, Jiahuan and Xiao, Xingqing and Liang, Xiaodong and Solms, Nicolas and Huo, Feng and He, Hongyan and Zhang, Suojiang}, year={2019}, month={Sep}, pages={19216–19225} } @article{xiao_kuang_slocik_tadepalli_brothers_kim_mirau_butkus_farmer_singamaneni_et al._2018, title={Advancing Peptide-Based Biorecognition Elements for Biosensors Using in-Silico Evolution}, volume={3}, ISSN={["2379-3694"]}, DOI={10.1021/acssensors.8b00159}, abstractNote={Sensors for human health and performance monitoring require biological recognition elements (BREs) at device interfaces for the detection of key molecular biomarkers that are measurable biological state indicators. BREs, including peptides, antibodies, and nucleic acids, bind to biomarkers in the vicinity of the sensor surface to create a signal proportional to the biomarker concentration. The discovery of BREs with the required sensitivity and selectivity to bind biomarkers at low concentrations remains a fundamental challenge. In this study, we describe an in-silico approach to evolve higher sensitivity peptide-based BREs for the detection of cardiac event marker protein troponin I (cTnI) from a previously identified BRE as the parental affinity peptide. The P2 affinity peptide, evolved using our in-silico method, was found to have ∼16-fold higher affinity compared to the parent BRE and ∼10 fM (0.23 pg/mL) limit of detection. The approach described here can be applied towards designing BREs for other biomarkers for human health monitoring.}, number={5}, journal={ACS SENSORS}, author={Xiao, Xingqing and Kuang, Zhifeng and Slocik, Joseph M. and Tadepalli, Sirimuvva and Brothers, Michael and Kim, Steve and Mirau, Peter A. and Butkus, Claire and Farmer, Barry L. and Singamaneni, Srikanth and et al.}, year={2018}, month={May}, pages={1024–1031} } @article{zhou_su_chen_xiao_qin_yang_yan_sun_2018, title={Capture of pure toxic gases through porous materials from molecular simulations}, volume={116}, ISSN={["1362-3028"]}, DOI={10.1080/00268976.2018.1440019}, abstractNote={ABSTRACT In the last three decades, the air pollution is the main problem to affect human health and the environment in China and its contaminants include SO2, NH3, H2S, NO2, NO and CO. In this work, we employed grand canonical Monte Carlo simulations to investigate the adsorption capability of metal-organic frameworks (MOFs) and covalent organic frameworks (COFs) for these toxic gases. Eighty-nine MOFs and COFs were studied, and top-10 adsorption materials were screened for each toxic gas at room temperature. Dependence of the adsorption performance on the geometry and constructed element of MOFs/COFs was determined and the adsorption conditions were optimised. The open metal sites have mainly influenced the adsorption of NH3, H2S, NO2 and NO. Especially, the X-DOBDC and XMOF-74 (X = Mg, Co, Ni, Zn) series of materials containing open metal sites are all best performance for adsorption of NH3 to illustrate the importance of electrostatic interaction. Our simulation results also showed that ZnBDC and IRMOF-13 are good candidates to capture the toxic gases NH3, H2S, NO2, NO and CO. This work provides important insights in screening MOF and COF materials with satisfactory performance for toxic gas removal.}, number={15-16}, journal={MOLECULAR PHYSICS}, author={Zhou, Xumiao and Su, Zejun and Chen, Houyang and Xiao, Xingqing and Qin, Yuanhang and Yang, Li and Yan, Zhiguo and Sun, Wei}, year={2018}, pages={2095–2107} } @article{kang_xiao_huang_yuan_tang_dai_zeng_2018, title={Potent aromatase inhibitors and molecular mechanism of inhibitory action}, volume={143}, ISSN={["1768-3254"]}, DOI={10.1016/j.ejmech.2017.11.057}, abstractNote={Estrogen is a significant factor in the maintenance and progression of hormone-dependent breast cancer. As well known, aromatase mediates the production of estrogen. Thus, inhibition of aromatase with chemical molecules has been considered to be an effective treatment for estrogen receptor-positive (ER+) breast cancer. In this work, we designed and synthesized a series of novel non-steroidal molecules containing 2-phenylindole scaffold and moiety of either imidazole or 1,2,4-triazole to enhance their binding capacity with the aromatase. Among these molecules, a compound named as 8o was confirmed experimentally to have the highest inhibitory activity to aromatase. Further cell activity assay proved that compound 8o has low cytotoxicity and is a promising lead for developing novel aromatase inhibitors. Molecular modeling and simulation techniques were performed to identify the binding modes of letrozole and 8o with the aromatase. Analysis of energy of the two compound-aromatase complexes revealed that the 8o has low binding energy (strong binding affinity) to the aromatase as compared to letrozole, which was in accordance with the experimental results. As concluded, a combination of experimental and computational approaches facilitates us to understand the molecular mechanism of inhibitory action and discover more potent non-steroidal AIs against aromatase, thereby opening up a novel therapeutic strategy for hormone-dependent breast cancer.}, journal={EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY}, author={Kang, Hongjun and Xiao, Xingqing and Huang, Chao and Yuan, Yan and Tang, Dongyan and Dai, Xiaochang and Zeng, Xianghui}, year={2018}, month={Jan}, pages={426–437} } @article{xiao_wang_leonard_hall_2017, title={Extended Concerted Rotation Technique Enhances the Sampling Efficiency of the Computational Peptide-Design Algorithm}, volume={13}, ISSN={["1549-9626"]}, DOI={10.1021/acs.jctc.7b00714}, abstractNote={To enhance the sampling efficiency of our computational peptide-design algorithm in conformational space, the concerted rotation (CONROT) technique is extended to enable larger conformational perturbations of peptide chains. This allows us to make relatively large peptide conformation changes during the process of designing peptide sequences to bind with high affinity to a specific target. Searches conducted using the new algorithm identified six potential λ N(2-22) peptide variants, called B1-B6, which bind to boxB RNA with high affinity. The results of explicit-solvent atomistic molecular dynamics simulations revealed that four of the evolved peptides, viz. B1, B2, B3, and B5, are excellent candidate binders to the target boxB RNA as they have lower binding free energies than the original λ N(2-22) peptide. Three of the four peptides, B2, B3, and B5, result from searches that contain both sequence and conformation changes, indicating that adding backbone motif changes to the peptide-design algorithm improves its performance considerably.}, number={11}, journal={JOURNAL OF CHEMICAL THEORY AND COMPUTATION}, author={Xiao, Xingqing and Wang, Yiming and Leonard, Joshua N. and Hall, Carol K.}, year={2017}, month={Nov}, pages={5709–5720} } @article{xiao_hung_leonard_hall_2016, title={Adding energy minimization strategy to peptide-design algorithm enables better search for RNA-binding peptides: Redesigned N peptide binds boxB RNA}, volume={37}, ISSN={["1096-987X"]}, DOI={10.1002/jcc.24466}, abstractNote={Our previously developed peptide‐design algorithm was improved by adding an energy minimization strategy which allows the amino acid sidechains to move in a broad configuration space during sequence evolution. In this work, the new algorithm was used to generate a library of 21‐mer peptides which could substitute for λ N peptide in binding to boxB RNA. Six potential peptides were obtained from the algorithm, all of which exhibited good binding capability with boxB RNA. Atomistic molecular dynamics simulations were then conducted to examine the ability of the λ N peptide and three best evolved peptides, viz. Pept01, Pept26, and Pept28, to bind to boxB RNA. Simulation results demonstrated that our evolved peptides are better at binding to boxB RNA than the λ N peptide. Sequence searches using the old (without energy minimization strategy) and new (with energy minimization strategy) algorithms confirm that the new algorithm is more effective at finding good RNA‐binding peptides than the old algorithm. © 2016 Wiley Periodicals, Inc.}, number={27}, journal={JOURNAL OF COMPUTATIONAL CHEMISTRY}, author={Xiao, Xingqing and Hung, Michelle E. and Leonard, Joshua N. and Hall, Carol K.}, year={2016}, month={Oct}, pages={2423–2435} } @article{xu_xiao_xu_liu_2016, title={Computational insights into the destabilization of alpha-helical conformations formed by leucine zipper peptides in response to temperature}, volume={18}, ISSN={["1463-9084"]}, DOI={10.1039/c6cp05145f}, abstractNote={The computed transition temperature of leucine zipper peptides is 319.1 K, which is in quantitative agreement with the experimental measurement, 321.1 K.}, number={36}, journal={PHYSICAL CHEMISTRY CHEMICAL PHYSICS}, author={Xu, Xiejun and Xiao, Xingqing and Xu, Shouhong and Liu, Honglai}, year={2016}, month={Sep}, pages={25465–25473} } @article{xiao_agris_hall_2016, title={Introducing folding stability into the score function for computational design of RNA-binding peptides boosts the probability of success}, volume={84}, ISSN={["1097-0134"]}, DOI={10.1002/prot.25021}, abstractNote={ABSTRACT}, number={5}, journal={PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS}, author={Xiao, Xingqing and Agris, Paul F. and Hall, Carol K.}, year={2016}, month={May}, pages={700–711} } @article{xiao_zhao_yang_liang_ren_2016, title={Probe the Binding Mode of Aristololactam-beta-D-glucoside to Phenylalanine Transfer RNA in Silico}, volume={1}, ISSN={["2365-6549"]}, DOI={10.1002/slct.201600603}, abstractNote={Abstract}, number={17}, journal={CHEMISTRYSELECT}, author={Xiao, Xingqing and Zhao, Binwu and Yang, Li and Liang, Xiaodong and Ren, Yingqian}, year={2016}, month={Oct}, pages={5430–5439} } @article{xiao_zhao_agris_hall_2016, title={Simulation study of the ability of a computationally-designed peptide to recognize target tRNA(Lys3) and other decoy tRNAs}, volume={25}, ISSN={["1469-896X"]}, DOI={10.1002/pro.3056}, abstractNote={Abstract}, number={12}, journal={PROTEIN SCIENCE}, author={Xiao, Xingqing and Zhao, Binwu and Agris, Paul F. and Hall, Carol K.}, year={2016}, month={Dec}, pages={2243–2255} } @article{xiao_agris_hall_2015, title={Designing Peptide Sequences in Flexible Chain Conformations to Bind RNA: A Search Algorithm Combining Monte Carlo, Self-Consistent Mean Field and Concerted Rotation Techniques}, volume={11}, ISSN={["1549-9626"]}, DOI={10.1021/ct5008247}, abstractNote={A search algorithm combining Monte Carlo, self-consistent mean field, and concerted rotation techniques was developed to discover peptide sequences that are reasonable HIV drug candidates due to their exceptional binding to human tRNAUUU(Lys3), the primer of HIV replication. The search algorithm allows for iteration between sequence mutations and conformation changes during sequence evolution. Searches conducted for different classes of peptides identified several potential peptide candidates. Analysis of the energy revealed that the asparagine and cysteine at residues 11 and 12 play important roles in "recognizing" tRNA(Lys3) via van der Waals interactions, contributing to binding specificity. Arginines preferentially attract the phosphate linkage via charge-charge interaction, contributing to binding affinity. Evaluation of the RNA/peptide complex's structure revealed that adding conformation changes to the search algorithm yields peptides with better binding affinity and specificity to tRNA(Lys3) than a previous mutation-only algorithm.}, number={2}, journal={JOURNAL OF CHEMICAL THEORY AND COMPUTATION}, author={Xiao, Xingqing and Agris, Paul F. and Hall, Carol K.}, year={2015}, month={Feb}, pages={740–752} } @article{xiao_zhao_ren_2015, title={Effect of curvature on properties of diblock copolymers confined between two coaxial cylinders: 1. Layer thickness of a curved monolayer}, volume={633}, ISSN={["1873-4448"]}, DOI={10.1016/j.cplett.2015.05.016}, abstractNote={Strong segregation limited theory was employed to deduce the expression for free energy of a curved (A–B) monolayer that is a basic repeating unit in multi-layered concentric structure. The free energy of the monolayer in different curved conditions can be evaluated. Using such cylindrical confinement model, we examined the influences of asymmetry of diblock copolymers on the layer thickness of a curved monolayer. For the diblock copolymers of f = 0.4, the optimal thickness has a slight increase and then decrease as the curvature increases; while for f = 0.6, the optimal thickness has a continuous decrease as the curvature increases.}, journal={CHEMICAL PHYSICS LETTERS}, author={Xiao, Xingqing and Zhao, Binwu and Ren, Yingqian}, year={2015}, month={Jul}, pages={58–64} } @article{xiao_zhao_yang_ren_2015, title={Effect of curvature on properties of diblock copolymers confined between two coaxial cylinders: 2. Domain adjustment in a curved bilayer}, volume={639}, ISSN={["1873-4448"]}, DOI={10.1016/j.cplett.2015.10.032}, abstractNote={We study the phase behavior of diblock copolymers in a curved bilayer. Three aspects are discussed in detail: domain size distributions of the two adjacent monolayers within the film, optimal film thickness for a bilayer, and structural transition from a monolayer to a bilayer. One major finding is the determination of transition point in film thickness where the layer-type structure goes from monolayer to bilayer. At high confinement, the transition point increases as the curvature increases regardless of the symmetry of diblock copolymers. At low confinement, the transition point might increase or decrease, depending on the symmetry of diblock copolymers.}, journal={CHEMICAL PHYSICS LETTERS}, author={Xiao, Xingqing and Zhao, Binwu and Yang, Li and Ren, Yingqian}, year={2015}, month={Oct}, pages={326–334} } @article{xiao_agris_hall_2015, title={Molecular recognition mechanism of peptide chain bound to the tRNA(Lys3) anticodon loop in silico}, volume={33}, ISSN={["1538-0254"]}, DOI={10.1080/07391102.2013.869660}, abstractNote={The mechanism by which proteins recognize and bind the post-transcriptional modifications of RNAs is unknown, yet these interactions play important functions in biology. Atomistic molecular dynamics simulations were performed to examine the folding of the model peptide chain –RVTHHAFLGAHRTVG– and the complex formed by the folded peptide with the native anticodon stem and loop of the human tRNALys3 (hASLLys3) in order to explore the binding mechanism. By analyzing and comparing two folded conformations of this peptide obtained from the folding simulation, we found that the van der Waals (VDW) energy is necessary for the thermal stability of the peptide, and the charge–charge (ELE + EGB) energy is crucial for determining the three-dimensional folded structure of the peptide backbone. Subsequently, two conformations of the peptide were employed to investigate their binding behaviors to hASLLys3. The metastable folded peptide was found to bind to hASLLys3 much easier than the stable folded peptide in the binding simulations. An energetic analysis reveals that the VDW energy favors the binding, whereas the ELE + EGB energies disfavor the binding. Arginines on the peptide preferentially attract the phosphate backbone via the inter-chain ELE + EGB interaction, significantly contributing to the binding affinity. The hydrophobic phenylalanine interacts with the anticodon loop of hASLLys3 via the inter-chain VDW interaction, significantly contributing to the binding specificity.}, number={1}, journal={JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS}, author={Xiao, Xingqing and Agris, Paul F. and Hall, Carol K.}, year={2015}, month={Jan}, pages={14–27} } @article{curtis_xiao_sofou_hall_2015, title={Phase Separation Behavior of Mixed Lipid Systems at Neutral and Low pH: Coarse-Grained Simulations with DMD/LIME}, volume={31}, ISSN={["0743-7463"]}, DOI={10.1021/la504082x}, abstractNote={We extend LIME, an intermediate resolution, implicit solvent model for phospholipids previously used in discontinuous molecular dynamics simulations of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayer formation at 325 K, to the description of the geometry and energetics of 1,2-distearoyl-sn-glycero-3-phospho-l-serine (DSPS) and 1,2-dihenarachidoyl-sn-glycero-3-phosphocholine (21PC) and mixtures thereof at both neutral and low pH at 310 K. A multiscale modeling approach is used to calculate the LIME parameters from atomistic simulation data on a mixed DPPC/DSPS system at different pH values. In the model, 17 coarse-grained sites represent DSPS and 18 coarse-grained sites represent 21PC. Each of these coarse-grained sites is classified as 1 of 9 types. LIME/DMD simulations of equimolar bilayers show the following: (1) 21PC/DSPS bilayers with and without surface area restrictions separate faster at low pH than at neutral pH, (2) 21PC/DSPS systems separate at approximately the same rate regardless of whether they are subjected to surface area restrictions, and (3) bilayers with a molar ratio of 9:1 (21PC:DSPS) phase separate to form heterogeneous domains faster at low pH than at neutral pH. Our results are consistent with experimental findings of Sofou and co-workers (Bandekar et al. Mol. Pharmaceutics, 2013, 10, 152–160; Karve et al. Biomaterials, 2010, 31, 4409–4416) that more doxorubicin is released from 21PC/DSPS liposomes at low pH than at neutral pH, presumably because greater phase separation is achieved at low pH than at neutral pH. These are the first molecular-level simulations of the phase separation in mixed lipid bilayers induced by a change in pH.}, number={3}, journal={LANGMUIR}, author={Curtis, Emily M. and Xiao, Xingqing and Sofou, Stavroula and Hall, Carol K.}, year={2015}, month={Jan}, pages={1086–1094} } @article{spears_xiao_hall_agris_2014, title={Amino Acid Signature Enables Proteins to Recognize Modified tRNA}, volume={53}, ISSN={0006-2960 1520-4995}, url={http://dx.doi.org/10.1021/bi401174h}, DOI={10.1021/bi401174h}, abstractNote={Human tRNALys3UUU is the primer for HIV replication. The HIV-1 nucleocapsid protein, NCp7, facilitates htRNALys3UUU recruitment from the host cell by binding to and remodeling the tRNA structure. Human tRNALys3UUU is post-transcriptionally modified, but until recently, the importance of those modifications in tRNA recognition by NCp7 was unknown. Modifications such as the 5-methoxycarbonylmethyl-2-thiouridine at anticodon wobble position-34 and 2-methylthio-N6-threonylcarbamoyladenosine, adjacent to the anticodon at position-37, are important to the recognition of htRNALys3UUU by NCp7. Several short peptides selected from phage display libraries were found to also preferentially recognize these modifications. Evolutionary algorithms (Monte Carlo and self-consistent mean field) and assisted model building with energy refinement were used to optimize the peptide sequence in silico, while fluorescence assays were developed and conducted to verify the in silico results and elucidate a 15-amino acid signature sequence (R-W-Q/N-H-X2-F-Pho-X-G/A-W-R-X2-G, where X can be most amino acids, and Pho is hydrophobic) that recognized the tRNA’s fully modified anticodon stem and loop domain, hASLLys3UUU. Peptides of this sequence specifically recognized and bound modified htRNALys3UUU with an affinity 10-fold higher than that of the starting sequence. Thus, this approach provides an effective means of predicting sequences of RNA binding peptides that have better binding properties. Such peptides can be used in cell and molecular biology as well as biochemistry to explore RNA binding proteins and to inhibit those protein functions.}, number={7}, journal={Biochemistry}, publisher={American Chemical Society (ACS)}, author={Spears, Jessica L. and Xiao, Xingqing and Hall, Carol K. and Agris, Paul F.}, year={2014}, month={Feb}, pages={1125–1133} } @article{xiao_hall_agris_2014, title={The design of a peptide sequence to inhibit HIV replication: a search algorithm combining Monte Carlo and self-consistent mean field techniques}, volume={32}, ISSN={["1538-0254"]}, DOI={10.1080/07391102.2013.825757}, abstractNote={We developed a search algorithm combining Monte Carlo (MC) and self-consistent mean field techniques to evolve a peptide sequence that has good binding capability to the anticodon stem and loop (ASL) of human lysine tRNA species, tRNALys3, with the ultimate purpose of breaking the replication cycle of human immunodeficiency virus-1. The starting point is the 15-amino-acid sequence, RVTHHAFLGAHRTVG, found experimentally by Agris and co-workers to bind selectively to hypermodified tRNALys3. The peptide backbone conformation is determined via atomistic simulation of the peptide-ASLLys3 complex and then held fixed throughout the search. The proportion of amino acids of various types (hydrophobic, polar, charged, etc.) is varied to mimic different peptide hydration properties. Three different sets of hydration properties were examined in the search algorithm to see how this affects evolution to the best-binding peptide sequences. Certain amino acids are commonly found at fixed sites for all three hydration states, some necessary for binding affinity and some necessary for binding specificity. Analysis of the binding structure and the various contributions to the binding energy shows that: 1) two hydrophilic residues (asparagine at site 11 and the cysteine at site 12) “recognize” the ASLLys3 due to the VDW energy, and thereby contribute to its binding specificity and 2) the positively charged arginines at sites 4 and 13 preferentially attract the negatively charged sugar rings and the phosphate linkages, and thereby contribute to the binding affinity.}, number={10}, journal={JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS}, author={Xiao, Xingqing and Hall, Carol K. and Agris, Paul F.}, year={2014}, pages={1523–1536} }