2021 Annual Meeting

(637b) Development of a Coarse Grained Discontinuous Molecular Dynamics Forcefield for Peptoids

Authors

Santiso, E., NC State University
Peptoids, or poly N-substituted glycines, are synthetic biocompatible peptidomimetics which have been used to develop antimicrobial agents, lung surfactants and drug delivery vehicles. They are protease resistant and have enhanced cellular uptake, which further make them attractive candidates for biological applications. Since peptoids lack native backbone hydrogens connected to an electronegative atom and hence lack backbone hydrogen bonding, their secondary structure is governed primarily by steric interactions (in the absence of specific interactions between side chains). Furthermore, unlike peptides, which have trans configuration as the prevalent amide bond isomer, peptoid amide bonds can have both cis- and trans- configurations. This allows for peptoids to exhibit a variety of secondary structures that are not observed in peptides.

Due to these differences and the varied accessible secondary structures between peptoids and peptides, force fields fitted for peptides have very limited applicability for peptoids. Weiser and Santiso [1] recently developed an atomistic force field for peptoids based on CGenFF, NTOID, which has the capability to model peptoids with amide bonds in the cis- and trans- conformation. In this work, we present an extension of this approach to develop coarse-grained models for use in discontinuous molecular dynamics (DMD) simulations.

We focus on discontinuous molecular dynamics because it is inherently faster than molecular dynamics and has been previously used for combinatorial screening of peptides. In order to develop our coarse-grained models, we use the relative entropy minimization method [2] to obtain bonded interaction parameters, using NTOID as the reference potential for which we implement a square well potential module in the software package VOTCA. For the intermolecular interaction parameters, we use a top-down coarse-graining approach using the square-well SAFT-γ equation of state [3] as implemented in the software package DESPASITO.

References:

[1] L.J. Weiser and E.E. Santiso, J. Comput. Chem. 40, 1946 (2019)

[2] M.S. Shell, Adv. Chem. Phys. 161, 395 (2016)

[3] A. Lymperiadis, C.S. Adjiman, G. Jackson, A. Galindo, Fluid Phase Eq. 274, 85 (2008)