Detailed Atomistic Molecular Dynamics Simulations of α-Conotoxin AuIB in Water

Abstract

We present results about the shape, size, structure, conformational stability, and hydrodynamics of alpha-conotoxin AuIB (a disulfide-rich peptide from the venom of Conus aulicus, recognized as a nicotinic acetylcholine antagonist with great pharmaceutical potential) from very long (0.5 mus) massively parallel molecular dynamics (MD) simulations in full atomistic detail. We extract coarse-grained descriptors of protein shape (ellipsoid), and of translational and rotational mobilities, i.e., the basic components at the lowest hierarchical level in a multiscale modeling strategy. Structural analysis reveals the folded conformation and asymmetric shape to be strongly favored for conotoxin. In accordance with experimental findings, conformational stability is observed and found to be linked to the presence of the alpha-helix along the 15 residues and to the existence of the two disulfide bonds. We find rotational (D(r)) and translational (D(t)) diffusivities to be suitable descriptors of coarse-grained dynamics, i.e., of the hydrodynamic behavior, and obtain D(r) = 3.62 (+/-0.17) x 10(8) s(- 1) and D(t) = 1.08 (+/-0.4) x 10(- 10) m(2) s(- 1). We further compare the MD-computed coarse-grained descriptors with first principles theoretical predictions based on the extended Hess-Doi Fokker-Planck approach which relates particle shape and dimensions to diffusion coefficients. An excellent agreement between simulation data and analytical predictions is observed for both dynamical descriptors. This comparison strongly suggests that diffusivities of rigid biomolecules much larger than the alpha-conotoxin AuIB studied here can be obtained from the coarse-grained shape descriptor (ellipsoid) derived from relatively short MD simulations.

Spontaneous Crystallization in Athermal Polymer Packings

“…Equation 1 is written in dimensionless form. The mass moment of inertia tensor provides a quantitative description of the shape of a rigid body and of the spatial distribution of its mass [89,118–120]. The internal, co-moving principal axis system of the Voronoi polyhedron is defined by the normalized eigenvectors ( e 1 , e 2, e 3 ).…”

Scrambling of disulfide bond scaffolds in neurotoxin AuIB: A molecular dynamics simulation study

“…This observation is similar to the previous results of Laso et al, who studied the native conformation of AuIB in water over a significantly long period of 0.5 ls. 25 Figure 2b shows a comparison of the RMSF values for N, P 2-8 , P 3-15 , and D. Presence of only one disulfide bond in the peptides P 2-8 and P 3-15 make them more labile, thereby increasing the overall RMSF values. However, a common region of 'least fluctuation' involving the residues Tyr-5 to Asn-12 may be noted in all the four peptide cases.…”

“…Hence, computer simulation has become an indispensable tool to study the shape, size, conformational stability, hydrodynamic behavior, folding patterns, and denaturation of such peptides. [24][25][26] So far, about 500 different types of cone snail species are reported. The pioneering work of characterization of cone snail venoms was done by Spence et al 27 They studied the venom from Conus geographus, purified it and attempted to determine its amino acid composition.…”

Snails In Silico: A Review of Computational Studies on the Conopeptides

“…Although fewer studies have been performed in this area, the number of such studies has increased in recent years. For example, Jiang and Ma [156] performed folding studies on α-GI with simplified quantum chemical computations and proved their usefulness in rapid simulations of folding/unfolding, while Karayiannis et al [157] harvested trajectories from long parallel MD simulations of α-AuIB to quantitatively characterize its structural and dynamic properties: the fluctuations of its size and shape and its translational and rotational diffusivities in water. An interesting recent study done by Jain and Pirogova [158] probed the effects of electric field strength on the conformations taken on by MrIIIe in solution.…”