Peptoid Conformational Free Energy Landscapes From Implicit-Solvent Molecular Simulations in AMBER Vincent A. Voelz, 1,2 * Ken A. Dill, 3 Ilya Chorny 1 1 Simprota Corporation, San Francisco, CA 2 Department of Chemistry, Stanford University, Stanford, CA 3 Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA Received 16 October 2010; revised 19 November 2010; accepted 2 December 2010 Published online 23 December 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/bip.21575 This article was originally published online as an accepted preprint. The ‘‘Published Online’’ date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com INTRODUCTION P eptoids (oligo N-substituted glycines) have chemical properties similar to peptides and been the subject of widespread interest for their biomimetic properties, 1 with applications as pharmaceuticals, 2 drug-delivery technology, 3 antimicrobials, 4,5 nano- technology, 6 and novel materials. 7 Polypeptoids are relatively easy to synthesize, resistant to proteolytic cleavage in the cell, and—despite the lack of backbone hydrogen bonds— can exhibit foldamer properties. 8 Although the peptoid Peptoid Conformational Free Energy Landscapes From Implicit-Solvent Molecular Simulations in AMBER Correspondence to: Vincent A. Voelz; e-mail: vvoelz@stanford.edu *Present affiliation: Department of Chemistry, Temple University, Philadelphia, PA ABSTRACT: To test the accuracy of existing AMBER force field models in predicting peptoid conformation and dynamics, we simulated a set of model peptoid molecules recently examined by Butterfoss et al. (JACS 2009, 131, 16798– 16807) using QM methods as well as three peptoid sequences with experimentally determined structures. We found that AMBER force fields, when used with a Generalized Born/Surface Area (GBSA) implicit solvation model, could accurately reproduce the peptoid torsional landscape as well as the major conformers of known peptoid structures. Enhanced sampling by replica exchange molecular dynamics (REMD) using temperatures from 300 to 800 K was used to sample over cis–trans isomerization barriers. Compared to (Nrch) 5 and cyclo-octasarcosyl, the free energy of N-(2-nitro-3- hydroxyl phenyl)glycine–N-(phenyl)glycine has the most ‘‘foldable’’ free energy landscape, due to deep trans-amide minima dictated by N-aryl sidechains. For peptoids with (S)-N(1-phenylethyl) (Nspe) side chains, we observe a discrepancy in backbone dihedral propensities between molecular simulations and QM calculations, which may be due to force field effects or the inability to capture n ? p* interactions. For these residues, an empirical u- angle biasing potential can ‘‘rescue’’ the backbone propensities seen in QM. This approach can serve as a general strategy for addressing force fields without resorting to a complete reparameterization. Overall, this study demonstrates the utility of implicit–solvent REMD simulations for efficient sampling to predict peptoid conformational landscapes, providing a potential tool for first-principles design of sequences with specific folding properties. # 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 639–650, 2011. Keywords: peptoid foldamer; computational chemistry; molecular simulation Contract grant sponsor: DARPA Contract grant number: W911NF-09-C-0087-SUB001 V V C 2010 Wiley Periodicals, Inc. PeptideScience Volume 96 / Number 5 639