Insights from molecular dynamics simulations for computational protein design

Abstract

A grand challenge in the field of structural biology is to design and engineer proteins that exhibit targeted functions. Although much success on this front has been achieved, design success rates remain low, an ever-present reminder of our limited understanding of the relationship between amino acid sequences and the structures they adopt. In addition to experimental techniques and rational design strategies, computational methods have been employed to aid in the design and engineering of proteins. Molecular dynamics (MD) is one such method that simulates the motions of proteins according to classical dynamics. Here, we review how insights into protein dynamics derived from MD simulations have influenced the design of proteins. One of the greatest strengths of MD is its capacity to reveal information beyond what is available in the static structures deposited in the Protein Data Bank. In this regard simulations can be used to directly guide protein design by providing atomistic details of the dynamic molecular interactions contributing to protein stability and function. MD simulations can also be used as a virtual screening tool to rank, select, identify, and assess potential designs. MD is uniquely poised to inform protein design efforts where the application requires realistic models of protein dynamics and atomic level descriptions of the relationship between dynamics and function. Here, we review cases where MD simulations was used to modulate protein stability and protein function by providing information regarding the conformation(s), conformational transitions, interactions, and dynamics that govern stability and function. In addition, we discuss cases where conformations from protein folding/unfolding simulations have been exploited for protein design, yielding novel outcomes that could not be obtained from static structures.

Engineered control of enzyme structural dynamics and function

“…5), the nature of the catalyzed chemical reaction (e.g., Ref. 6), and/or the enzyme's physiochemical properties (e.g., temperature stability 7 ). In this review, we note many of the ways that protein structural dynamics can be altered to modify enzyme function, including site mutations, protein hybrids and other post-translational chemical modifications.…”

Recent advances in automated protein design and its future challenges

“…The main challenge is dealing with the (many) transition states and intermediates involved in a catalytic cycle, which require a hybrid quantum mechanics and molecular mechanics approach using (QM/MM) modeling [70] and molecular dynamics (MD) simulations [71]. In 2012, Mayo and coworkers demonstrated an iterative design guided by MD simulations and experiments, giving a major improvement in the design of Kemp-elimination enzyme [72].…”

Modeling Soft Supramolecular Nanostructures by Molecular Simulations

“…Other interesting example of application relates to protein-ligand interactions [103][104][105][106][107], which are typically pursued by significant conformational and energetic changes. These Representative conformation of the complex between PAZ domain of the human argonaute 2 (hAgo2) and the chemically modified siRNAs at 3′ overhang, obtained from the last nanoseconds of the MD production runs.…”