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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. 

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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. 

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3. Simulation Data for Design of Peptides that Fold and Self-Assemble on Graphite

   https://doi.org/10.5281/zenodo.6426152  

   Comer, Jeffrey ; Thakkar, Ravindra ; Velásquez-Silva, Astrid ; Miranda-Carvajal, Ingrid ( January 2022 , Zenodo)

   This data set for the manuscript entitled "Design of Peptides that Fold and Self-Assemble on Graphite" includes all files needed to run and analyze the simulations described in the this manuscript in the molecular dynamics software NAMD, as well as the output of the simulations. The files are organized into directories corresponding to the figures of the main text and supporting information. They include molecular model structure files (NAMD psf or Amber prmtop format), force field parameter files (in CHARMM format), initial atomic coordinates (pdb format), NAMD configuration files, Colvars configuration files, NAMD log files, and NAMD output including restart files (in binary NAMD format) and trajectories in dcd format (downsampled to 10 ns per frame). Analysis is controlled by shell scripts (Bash-compatible) that call VMD Tcl scripts or python scripts. These scripts and their output are also included.

   Version: 2.0

   Changes versus version 1.0 are the addition of the free energy of folding, adsorption, and pairing calculations (Sim_Figure-7) and shifting of the figure numbers to accommodate this addition.

   
   Conventions Used in These Files
   ===============================

   Structure Files
   ----------------
   - graph_*.psf or sol_*.psf (original NAMD (XPLOR?) format psf file including atom details (type, charge, mass), as well as definitions of bonds, angles, dihedrals, and impropers for each dipeptide.)

   - graph_*.pdb or sol_*.pdb (initial coordinates before equilibration)
   - repart_*.psf (same as the above psf files, but the masses of non-water hydrogen atoms have been repartitioned by VMD script repartitionMass.tcl)
   - freeTop_*.pdb (same as the above pdb files, but the carbons of the lower graphene layer have been placed at a single z value and marked for restraints in NAMD)
   - amber_*.prmtop (combined topology and parameter files for Amber force field simulations)
   - repart_amber_*.prmtop (same as the above prmtop files, but the masses of non-water hydrogen atoms have been repartitioned by ParmEd)

   Force Field Parameters
   ----------------------
   CHARMM format parameter files:
   - par_all36m_prot.prm (CHARMM36m FF for proteins)
   - par_all36_cgenff_no_nbfix.prm (CGenFF v4.4 for graphene) The NBFIX parameters are commented out since they are only needed for aromatic halogens and we use only the CG2R61 type for graphene.
   - toppar_water_ions_prot_cgenff.str (CHARMM water and ions with NBFIX parameters needed for protein and CGenFF included and others commented out)

   Template NAMD Configuration Files
   ---------------------------------
   These contain the most commonly used simulation parameters. They are called by the other NAMD configuration files (which are in the namd/ subdirectory):
   - template_min.namd (minimization)
   - template_eq.namd (NPT equilibration with lower graphene fixed)
   - template_abf.namd (for adaptive biasing force)

   Minimization
   -------------
   - namd/min_*.0.namd

   Equilibration
   -------------
   - namd/eq_*.0.namd

   Adaptive biasing force calculations
   -----------------------------------
   - namd/eabfZRest7_graph_chp1404.0.namd
   - namd/eabfZRest7_graph_chp1404.1.namd (continuation of eabfZRest7_graph_chp1404.0.namd)

   Log Files
   ---------
   For each NAMD configuration file given in the last two sections, there is a log file with the same prefix, which gives the text output of NAMD. For instance, the output of namd/eabfZRest7_graph_chp1404.0.namd is eabfZRest7_graph_chp1404.0.log.

   Simulation Output
   -----------------
   The simulation output files (which match the names of the NAMD configuration files) are in the output/ directory. Files with the extensions .coor, .vel, and .xsc are coordinates in NAMD binary format, velocities in NAMD binary format, and extended system information (including cell size) in text format. Files with the extension .dcd give the trajectory of the atomic coorinates over time (and also include system cell information). Due to storage limitations, large DCD files have been omitted or replaced with new DCD files having the prefix stride50_ including only every 50 frames. The time between frames in these files is 50 * 50000 steps/frame * 4 fs/step = 10 ns. The system cell trajectory is also included for the NPT runs are output/eq_*.xst.

   Scripts
   -------
   Files with the .sh extension can be found throughout. These usually provide the highest level control for submission of simulations and analysis. Look to these as a guide to what is happening. If there are scripts with step1_*.sh and step2_*.sh, they are intended to be run in order, with step1_*.sh first.

   
   CONTENTS
   ========

   The directory contents are as follows. The directories Sim_Figure-1 and Sim_Figure-8 include README.txt files that describe the files and naming conventions used throughout this data set.

   Sim_Figure-1: Simulations of N-acetylated C-amidated amino acids (Ac-X-NHMe) at the graphite–water interface.

   Sim_Figure-2: Simulations of different peptide designs (including acyclic, disulfide cyclized, and N-to-C cyclized) at the graphite–water interface.

   Sim_Figure-3: MM-GBSA calculations of different peptide sequences for a folded conformation and 5 misfolded/unfolded conformations.

   Sim_Figure-4: Simulation of four peptide molecules with the sequence cyc(GTGSGTG-GPGG-GCGTGTG-SGPG) at the graphite–water interface at 370 K.

   Sim_Figure-5: Simulation of four peptide molecules with the sequence cyc(GTGSGTG-GPGG-GCGTGTG-SGPG) at the graphite–water interface at 295 K.

   Sim_Figure-5_replica: Temperature replica exchange molecular dynamics simulations for the peptide cyc(GTGSGTG-GPGG-GCGTGTG-SGPG) with 20 replicas for temperatures from 295 to 454 K.

   Sim_Figure-6: Simulation of the peptide molecule cyc(GTGSGTG-GPGG-GCGTGTG-SGPG) in free solution (no graphite).

   Sim_Figure-7: Free energy calculations for folding, adsorption, and pairing for the peptide CHP1404 (sequence: cyc(GTGSGTG-GPGG-GCGTGTG-SGPG)). For folding, we calculate the PMF as function of RMSD by replica-exchange umbrella sampling (in the subdirectory Folding_CHP1404_Graphene/). We make the same calculation in solution, which required 3 seperate replica-exchange umbrella sampling calculations (in the subdirectory Folding_CHP1404_Solution/). Both PMF of RMSD calculations for the scrambled peptide are in Folding_scram1404/. For adsorption, calculation of the PMF for the orientational restraints and the calculation of the PMF along z (the distance between the graphene sheet and the center of mass of the peptide) are in Adsorption_CHP1404/ and Adsorption_scram1404/. The actual calculation of the free energy is done by a shell script ("doRestraintEnergyError.sh") in the 1_free_energy/ subsubdirectory. Processing of the PMFs must be done first in the 0_pmf/ subsubdirectory. Finally, files for free energy calculations of pair formation for CHP1404 are found in the Pair/ subdirectory.

   Sim_Figure-8: Simulation of four peptide molecules with the sequence cyc(GTGSGTG-GPGG-GCGTGTG-SGPG) where the peptides are far above the graphene–water interface in the initial configuration.

   Sim_Figure-9: Two replicates of a simulation of nine peptide molecules with the sequence cyc(GTGSGTG-GPGG-GCGTGTG-SGPG) at the graphite–water interface at 370 K.

   Sim_Figure-9_scrambled: Two replicates of a simulation of nine peptide molecules with the control sequence cyc(GGTPTTGGGGGGSGGPSGTGGC) at the graphite–water interface at 370 K.

   Sim_Figure-10: Adaptive biasing for calculation of the free energy of the folded peptide as a function of the angle between its long axis and the zigzag directions of the underlying graphene sheet.

    

   This material is based upon work supported by the US National Science Foundation under grant no. DMR-1945589. A majority of the computing for this project was performed on the Beocat Research Cluster at Kansas State University, which is funded in part by NSF grants CHE-1726332, CNS-1006860, EPS-1006860, and EPS-0919443. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1548562, through allocation BIO200030. 

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4. 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.

    

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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)

   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.

    

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