Villin headpiece

REX-CPHMD simulations have also been applied to understand the mechanism of the formation of protein intermediate states. Recent solution NMR data revealed a sparsely populated intermediate in the villin headpiece domain, in which the N-terminal subdomain is largely random but the C-terminal subdomain adopts a nativelike fold [34], Interestingly, H41 in this intermediate state titrates at a pH value of... 

Another interesting application area of PHMD simulations is to investigate electrostatic interactions in the unfolded states of proteins. A traditional view that unfolded proteins adopt random conformational states that are devoid of electrostatic and hydrophobic interactions, are recently challenged by experimental data [20, 69], REX-CPHMD folding simulations of the 35 residue C-terminal subdomain of the villin headpiece domain revealed a significant deviation from the standard pKa values for several titratable residues. Additional simulations, in which a charged group is neutralized confirmed the existence of specific electrostatic interactions in the unfolded states (JK and CLB, manuscript in preparation). 

Khandogin J, Raleigh DP, Brooks CL III (2007) Folding intermediate in the villin headpiece domain arises from disruption of a N-terminal hydrogen-bonded network. J Am Chem Soc 129 3056-3057. 

We extrapolate from two simulations, the 10 ps simulation on bovine pancreatic trypsin inhibitor (BPTI) reported over twenty years ago [61] and the recent 1 gs simulation on the villin headpiece subdomain. [9] Each of these was a state-of-the-art simulation, using the best algorithms and the most powerful hardware available at the time. 

As in all computer applications for the past few decades, P has been growing exponentially with time. It is a straightforward calculation to show that in the 21 years between the BPTI simulation (t = KTns n 600) and the villin headpiece simulation (t = KT6 s n 12 000), P has been increasing by a factor of 10 every 3-4 years. A simple extrapolation would thus predict that a simulation covering the replication cyde of an intact E. coli with a volume of about 1 p3 (t 1000 s n=3x 1010) could be expected some time in the second half of the next century if computational power continued to grow exponentially at historical rates. 

Duan Y., Wang L. and Kouman P. A. The early stage of folding of villin headpiece sub-domain observed in a 200-nanosecond fully solvated molecular dynamics simulation. Proc. Natl. Acad. Sci., USA (1998) 95(17) 9897-9902. 

De Mori, G.M.S., Colombo, G., Micheletti, C. Study of the villin headpiece folding dynamics by combining coarse-grained Monte Carlo evolution and all-atom molecular dynamics. Protein. Struct. Funct. Genet. 2005, 58, 459-71. 

Lee MR, Duan Y, Kollman PA (2000) Use of MM-PB/SA in estimating the free energies of proteins application to native, intermediates, and unfolded villin headpiece, Proteins, 39(4) 309-316... 

Figure 1. Schematic domain structures are shown for homologous villidin proteins from D. d/sco/deum (XP 636652,1704aa) and E. histolytica ("ABPH", AF118397,1602aa). Both contain typical coronin domains at their amino termini in addition to 3 pleckstrin homology (PH), 3-5 gelsolin (C) and a villin headpiece (VHP) domains at the C-termini, all detected by matches to the corresponding hidden Markov models (HMM) from the PFAM database (http //www. sanger.ac.uk/Software/Pfam/).

Fernandez A, Shen M, Colubri A, Sosnick TR, Freed KF (2003) Large-scale context in protein folding Villin headpiece. Biochemistry 42 664-671... 

Fig. 6. Low-energy structure of the 36-residue chicken villin headpiece sub-domain HP-36. On the left the structure determined in NMR experiments is shown. The right panel shows the lowest-energy configuration found in a feedback-optimized allatom parallel tempering simulation using the ECEPP/2 force field and an implicit solvent model. The root-mean square deviation of this structure to the structure on the left is Rrmsd = 3.8 A...

The feedback-optimized parallel tempering technique [26] outlined in the previous section has recently been applied to study the folding of the 36-residue chicken villin headpiece sub-domain HP-36 [27]. Since HP-36 is one of the smallest proteins with well-defined secondary and tertiary structure [28] and at the same time with 596 atoms still accessible to numerical simulations, it has recently attracted considerable interest as an example to test novel numerical techniques, including molecular dynamics [29,30] and Monte Carlo [31,32] methods. The experimentally determined structure [28] which is deposited in the Protein Data Bank (PDB code Ivii) is illustrated in the left panel of Fig. 6. 

Fig. 7. Local diffusivity solid circles) of the random walk in temperature space for a parallel tempering simulation of the 36-residue villin headpiece sub-domain HP-36. The diffusivity shows a strong modulation along the temperature, note the logarithmic scale of the ordinate. Slightly below the helix-coil transition around T fs 500 K which is identified by a maximum in the specific heat (crosses, right ordinate) there is a strong suppression of the diffusivity...

The protein folding problem - the ability to predict a protein fold from its sequence - is one of the major prizes in computational chemistry. Molecular dynamics simulations of solvated proteins is currently not a feasible approach to this problem. However, Duan and Kollman have shown that a 1 ps simulation on a small hydrated protein, here the 36 residue villin headpiece, is now possible using a massively parallel super computer.33 The native protein is estimated to fold in about 10-100 ps and so the simulation can only be used to study the early stages of protein folding. Nevertheless, starting from an extended structure the authors were able to observe hydrophobic collapse and secondary structure formation (helix 2 was well formed, helices 1 and 3 were partially formed and the loop connecting helices 1 and 2 was also partially... 

Vugmeyster L, McKnight CJ (2008) Slow motions in Chicken Villin headpiece subdomain probed by cross-correlated NMR relaxation of amide NH bonds in successive residues. Biophys J 95 5941-5950... 

Figure 1.15 Experimental (red (dark grey in print version)) and simuiated (biue (grey in print version)) quadrupole echo line shapes for methyl groups in hydrated samples of the hydrophobic core of chicken villin headpiece subdomain. The variability in the line shapes reflects the differences in mobility on the ps-ms time sca e. Reprinted from [159]. Copyright 2011 American Chemical Society.

L. Vugmeyster, D. Ostrovsky, A. Khadjinova,. EUden, G.L. Hoatson, R.L. Void, Slow motions in the hydrophobic core of chicken villin headpiece subdomain and their contributions to configurational entropy and heat capacity from solid-state deuteron NMR measurements. Biochemistry 50 (2011) 10637—10646. 

Stage of Folding of Villin Headpiece Subdomain Observed in a 200-Nanosecond Fnlly Solvated Molecular Dynamic Simulation. 

ParsCompetition between tryptophan flumescence and electron transfer during unfolding of the villin headpiece. Biochemistry 53,4503-4509 (2014)... 

Tusell, J.R., Callis, P.R. Simulations of tryptophan fluorescence dynamics during folding of the villin headpiece. J. Phys. Chem. B 116, 2586-2594 (2012)... 

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