Relative stability of de novo four–helix bundle proteins: Insights from coarse grained molecular simulations

Abstract

We use a recently developed coarse-grained computational model to investigate the relative stability of two different sets of de novo designed four-helix bundle proteins. Our simulations suggest a possible explanation for the experimentally observed increase in stability of the four-helix bundles with increasing sequence length. In details, we show that both short subsequences composed only by polar residues and additional nonpolar residues inserted, via different point mutations in ad hoc positions, seem to play a significant role in stabilizing the fourhelix bundle conformation in the longer sequences. Finally, we propose an additional mutation that rescues a short amino acid sequence that would otherwise adopt a compact misfolded state. Our work suggests that simple computational models can be used as a complementary tool in the design process of de novo proteins.

Space Warping Order Parameters and Symmetry: Application to Multiscale Simulation of Macromolecular Assemblies

“…Consequently, computational cost of implementing these reduced dimensional models is moderate. A list of relevant approaches would include bead- and shape-based coarse-graining models, 14–16 rigid region decomposition, 17 symmetry constrained 18 and curvilinear coordinate 19 models, as well as principal component analysis (PCA) 20,21 and normal-mode analysis guided approaches. 22,23 These models have been successful in investigating structural transitions in a very rich set of biomolecular systems including BPTI, lysozyme, ligand-binding proteins, 24 trans-membrane proteins, 25 RNA segments, 20,26 GRoEL, 27 and viral protein capsids of different symmetries.…”

Physical properties of phospholipids and integral proteins and their biofunctional roles in pulmonary surfactant from molecular dynamics simulation

“…The sL and sH beads are mutually repulsive and differ only in the parameterization of their respective dihedral potentials. The coarse-grained protein scheme has also been well discussed in the literature by Monticelli et al 44 and in other work by Bellesia et al 45…”

Development of a High-Throughput Fluorescence Polarization Assay to Detect Inhibitors of the FAK–Paxillin Interaction

“…This DMSO tolerability may be due to the high thermostability of four-helical bundle proteins like the FAK FAT domain that have a high degree of hydrophobic packing and electrostatic interactions to stabilize 3D structure. 39 Note that in plate optimization studies, polypropylene plates seemed to correlate best with assay performance, perhaps due to the amphipathic nature of the LD2 peptide. Future studies may include further optimization of the TAMRA–LD2 probe to reduce potential aggregation or modification of the FAK protein construct (e.g., length) to allow greater mP change on binding.…”