More Like this

1. An Atomistic Investigation of Adsorption of Bone Morphogenetic Protein-2 on Gold with Nanoscale Topographies

   https://doi.org/10.3390/surfaces5010010  

   Marquetti, Izabele; Desai, Salil (March 2022, Surfaces)

   Nanoscale surface topographies mediated with biochemical cues influence the differentiation of stem cells into different lineages. This research focuses on the adsorption behavior of bone morphogenetic protein (BMP-2) on nanopatterned gold substrates, which can aid in the differentiation of bone and cartilage tissue constructs. The gold substrates were patterned as flat, pillar, linear grating, and linear-grating deep based, and the BMP-2 conformation in end-on configuration was studied over 20 ns. The linear grating deep substrate pattern had the highest adsorption energy of around 125 kJ/mol and maintained its radius of gyration of 18.5 Å, indicating a stable adsorption behavior. Secondary structures including α-helix and β-sheet displayed no denaturation, and thus, the bioavailability of the BMP-2, for the deep linear-grating pattern. Ramachandran plots for the wrist and knuckle epitopes indicated no steric hindrances and provided binding sites to type I and type II receptors. The deep linear-grating substrate had the highest number of contacts (88 atoms) within 5 Å of the gold substrate, indicating its preferred nanoscale pattern choice among the substrates considered. This research provides new insights into the atomistic adsorption of BMP-2 on nanoscale topographies of a gold substrate, with applications in biomedical implants and regenerative medicine. 

   more » « less
2. Orientation effects on the nanoscale adsorption behavior of bone morphogenetic protein-2 on hydrophilic silicon dioxide

   https://doi.org/10.1039/c8ra09165j  

   Marquetti, Izabele; Desai, Salil (January 2019, RSC Advances)

   Bone Morphogenetic Protein-2 (BMP-2) is a growth factor associated with different developmental functions in regenerative medicine and tissue engineering. Because of its favorable properties for the development of bone and cartilage tissue, BMP-2 promotes the biocompatibility of medical implants. In this research, molecular dynamics simulations were implemented to simulate the interaction of BMP-2 with a flat hydrophilic silicon dioxide substrate, an important biomaterial for medical applications. We considered the influence of four orthogonal protein orientations on the adsorption behavior. Results showed that arginine and lysine were the main residues to interact with the silicon dioxide substrate, directly adsorbing onto the surface and overcoming water layers. However, between these charged residues, we observed a preference for arginine to adsorb. Orientations with the α-helix loop closer to the surface at the beginning of the simulations had greater loss of secondary structure as compared to the other configurations. Among all the orientations, the end-on B configuration had favorable adsorption characteristics with a binding energy of 14 000 kJ mol −1 and retention of 21.7% β-sheets as confirmed by the Ramachandran plots. This research provides new insights into the nanoscale interaction of BMP-2 and silicon dioxide substrate with applications in orthopedic implants and regenerative medicine. 

   more » « less
3. SMOC-1 interacts with both BMP and glypican to regulate BMP signaling in C. elegans

   https://doi.org/10.1371/journal.pbio.3002272  

   DeGroot, Melisa S.; Williams, Byron; Chang, Timothy Y.; Maas Gamboa, Maria L.; Larus, Isabel M.; Hong, Garam; Fromme, J. Christopher; Liu, Jun (August 2023, PLOS Biology)

   Mullins, Mary C. (Ed.)

   Secreted modular calcium-binding proteins (SMOCs) are conserved matricellular proteins found in organisms fromCaenorhabditis elegansto humans. SMOC homologs characteristically contain 1 or 2 extracellular calcium-binding (EC) domain(s) and 1 or 2 thyroglobulin type-1 (TY) domain(s). SMOC proteins inDrosophilaandXenopushave been found to interact with cell surface heparan sulfate proteoglycans (HSPGs) to exert both positive and negative influences on the conserved bone morphogenetic protein (BMP) signaling pathway. In this study, we used a combination of biochemical, structural modeling, and molecular genetic approaches to dissect the functions of the sole SMOC protein inC.elegans. We showed that CeSMOC-1 binds to the heparin sulfate proteoglycan GPC3 homolog LON-2/glypican, as well as the mature domain of the BMP2/4 homolog DBL-1. Moreover, CeSMOC-1 can simultaneously bind LON-2/glypican and DBL-1/BMP. The interaction between CeSMOC-1 and LON-2/glypican is mediated specifically by the EC domain of CeSMOC-1, while the full interaction between CeSMOC-1 and DBL-1/BMP requires full-length CeSMOC-1. We provide both in vitro biochemical and in vivo functional evidence demonstrating that CeSMOC-1 functions both negatively in a LON-2/glypican-dependent manner and positively in a DBL-1/BMP-dependent manner to regulate BMP signaling. We further showed that in silico,Drosophilaand vertebrate SMOC proteins can also bind to mature BMP dimers. Our work provides a mechanistic basis for how the evolutionarily conserved SMOC proteins regulate BMP signaling. 

   more » « less
4. The competing influence of surface roughness, hydrophobicity, and electrostatics on protein dynamics on a self-assembled monolayer

   https://doi.org/10.1063/5.0078797  

   Misiura, Anastasiia; Dutta, Chayan; Leung, Wesley; Zepeda O, Jorge; Terlier, Tanguy; Landes, Christy F. (March 2022, The Journal of Chemical Physics)

   Surface morphology, in addition to hydrophobic and electrostatic effects, can alter how proteins interact with solid surfaces. Understanding the heterogeneous dynamics of protein adsorption on surfaces with varying roughness is experimentally challenging. In this work, we use single-molecule fluorescence microscopy to study the adsorption of α-lactalbumin protein on the glass substrate covered with a self-assembled monolayer (SAM) with varying surface concentrations. Two distinct interaction mechanisms are observed: localized adsorption/desorption and continuous-time random walk (CTRW). We investigate the origin of these two populations by simultaneous single-molecule imaging of substrates with both bare glass and SAM-covered regions. SAM-covered areas of substrates are found to promote CTRW, whereas glass surfaces promote localized motion. Contact angle measurements and atomic force microscopy imaging show that increasing SAM concentration results in both increasing hydrophobicity and surface roughness. These properties lead to two opposing effects: increasing hydrophobicity promotes longer protein flights, but increasing surface roughness suppresses protein dynamics resulting in shorter residence times. Our studies suggest that controlling hydrophobicity and roughness, in addition to electrostatics, as independent parameters could provide a means to tune desirable or undesirable protein interactions with surfaces. 

   more » « less
5. Seeding and cross‐seeding fibrillation of N‐terminal prion protein peptides PrP(120–144)

   https://doi.org/10.1002/pro.3421  

   Wang, Yiming; Hall, Carol K. (May 2018, Protein Science)

   Abstract Prion diseases are infectious neurodegenerative diseases that are capable of cross‐species transmission, thus arousing public health concerns. Seed‐templating propagation of prion protein is believed to underlie prion cross‐species transmission pathology. Understanding the molecular fundamentals of prion propagation is key to unravelling the pathology of prion diseases. In this study, we use coarse‐grained molecular dynamics to investigate the seeding and cross‐seeding aggregation of three prion protein fragments PrP(120–144) originating from human (Hu), bank vole (BV), and Syrian hamster (SHa). We find that the seed accelerates the aggregation of the monomer peptides by eliminating the lag phase. The monomer aggregation kinetics are mainly determined by the structure of the seed. The stronger the hydrophobic residues on the seed associate with each other, the higher the probability that the seed recruits monomer peptides to its surface/interface. For cross‐seeding aggregation, we show that Hu has a strong tendency to adopt the conformation of the BV seed and vice versa; the Hu and BV monomers have a weak tendency to adopt the conformation of the SHa seed. These two findings are consistent with Apostolet al.'s experimental findings on PrP(138–143) and partially consistent with Joneset al.'s finding on PrP(23–144). We also identify several conformational mismatches when SHa cross‐seeds BV and Hu peptides, indicating the existence of a cross‐seeding barrier between SHa and the other two sequences. This study sheds light on the molecular mechanism of seed‐templating aggregation of prion protein fragments underlying the sequence‐dependent transmission barrier in prion diseases. 

   more » « less