A promising new direction in drug design has been the development of peptidomimetic compounds that can target protein-protein interfaces (PPIs). For these systems, molecular simulation-based methods for designing pre-organized structure in solution would be highly desirable, but they remain challenging to implement due to the need for large-scale sampling of conformational and chemical space. Here we present new Markov State Model (MSM) approaches to the problem of simulation-based molecular design. First, we will discuss new analytical techniques we have developed to efficiently evaluate proposed designs by considering MSM rate perturbations. A relative entropy-like metric can be used to identify metastable conformational states most sensitive to perturbations, so that adaptive sampling can be focused there most efficiently. Next, we will discuss an extensive simulation study of designed cyclic peptide mimics of a �-hairpin from bacterial protein LapD involved in a PPI pertinent to bacterial biofilm formation. We used replica exchange molecular dynamics (REMD) simulation to screen twenty covalently cross-linked designs with varying stereochemistry, and selected the most favorable of these for massively parallel simulation on Folding@home. MSMs built from the trajectory data reveal how subtle chemical modifications can have a significant effect on conformational populations, leading to the overall stabilization of the target structure. In particular, we identify a key steric interaction between a methyl substituent and a valine sidechain that acts to allosterically shift population between native and near-native states, a feature that can be exploited in future designs. These conclusions would not be possible without the robust model construction and data visualization provided by the tICA method, which identifies degrees of freedom most important in slow conformational transitions. Overall, the combination of quantitative detail and human comprehension provided by MSMs suggests such approaches will be increasingly useful for peptidomimetic design.

Molecular simulation and kinetic network models: New tools for designing peptidomimetics

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.