Unraveling the Conformational Determinants of Peptide Dendrimers Using Molecular Dynamics Simulations

Abstract

Peptide dendrimers are synthetic tree-like molecules composed of amino acids. There are at least two kinds of preferential structural behaviors exhibited by these molecules, which acquire either compact or noncompact shapes. However, the key structural determinants of such behaviors remained, until now, unstudied. Herein, we conduct a comprehensive investigation of the structural determinants of peptide dendrimers by employing long molecular dynamics simulations to characterize an extended set of third generation dendrimers. Our results clearly show that a trade-off between electrostatic effects and hydrogen bond formation controls structure acquisition in these systems. Moreover, by selectively changing the dendrimers charge we are able to manipulate the exhibited compactness. In contrast, the length of branching residues does not seem to be a major structural determinant. Our results are in accordance with the most recent experimental evidence and shed some light on the key molecular level interactions controlling structure acquisition in these systems. Thus, the results presented constitute valuable insights that can contribute to the development of truly tailor-made dendritic systems.

Molecular Modeling to Study Dendrimers for Biomedical Applications

“…The force fields represent the potential energy and define the forces applied to the system (ensemble of N atoms), which includes the sum of bonded (bond-length, bond-angle, torsion terms) and non-bonded (electrostatic and van der Waals interactions). Commonly force fields that have been used for dendrimers include the AMBER [43,72], CHARMM [73,74,75], GROMOS [38,76], MARTINI [77,78,79] CVFF [80,81], OPLS [29,82,83] and DREIDING Force [84,85]. An overview of the different force fields applied to dendrimers can be seen in Table 1.…”

Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties

“…Depending on the dendrimer generation, simulations took between 5 and 25 ns to equilibrate, which is similar to other dendrimer simulations. 8 Therefore, the last 20 ns of each simulation was used to ensure that the equilibrated systems were used during the evaluation of the properties of PG dendrimers. Despite the possibility of dendrimers being highly flexible and that the RMSD might not by itself indicate that equilibration was truly reached, this sampling should be sufficient to account for the dynamic behavior of PG dendrimers.…”

“…20 Thus, designing dendrimers that have a defined number of probes that are hindered from the external environment is of uppermost importance. However, there is still an overall lack of knowledge of the behavior of these molecules at the atomistic level, 8 and consequently, computational methods can provide a suitable tool to explore the behavior of these macromolecules.…”

Optimizing the Multivalent Binding of the Bacterial Lectin LecA by Glycopeptide Dendrimers for Therapeutic Purposes

“…21,26 The 175 possible sequences have been constructed and simulated in explicit solvent for 5 ms. Quantifying differences between peptide structures is traditionally performed by computing the root mean-square deviation (RMSD) of the backbone atoms, after removal of rigid-body rotation and translation effects via least-square fitting; this approach has already been applied to peptidic dendrimers of varying sequences. 25 The methodology was adapted to the symmetric topology of the current dendrimers (see Methods for details). The 'central' structure of each dendrimer (whose RMSD to the average structure over the entire simulation is minimal) was extracted, and a square, symmetric, rank-175 similarity matrix was built from the RMSD values between the central structures of all possible dendrimer pairs.…”

“…As such, theoretical studies on the matter have mostly been used either as a posteriori validation of experimental results, 20 or to explore the effects of limited variations upon sequences gleaned from databases. [24][25][26] Coarse-grained models (in which atoms making up standalone chemical functions are grouped into beads) can be used to simulate much longer timescales than their all-atom counterparts for the same computational cost; this is not only due to the straightforward reduction in the dimensionality of the problem, but also to an effective kinetic speedup associated with the 'smoothing out' of local features on the energy landscape brought about by coarse-graining. 27 This study applies the MARTINI 28,29 coarse-grained model (which has been successfully applied to unstructured antimicrobial peptides in the past [30][31][32] ) and long-timescale molecular dynamics simulations to the systematic exploration of aminoacid sequence effects on the dynamics of octavalent peptide dendrimers functionalized with galactose, as well as their ability to bind the galactose-specific lectin LecA.…”