The stability and dynamics of computationally designed proteins

Abstract

Protein stability, dynamics and function are intricately linked. Accordingly, protein designers leverage dynamics in their designs and gain insight to their successes and failures by analyzing their proteins' dynamics. Molecular dynamics (MD) simulations are a powerful computational tool for quantifying both local and global protein dynamics. This review highlights studies where MD simulations were applied to characterize the stability and dynamics of designed proteins and where dynamics were incorporated into computational protein design. First, we discuss the structural basis underlying the extreme stability and thermostability frequently observed in computationally designed proteins. Next, we discuss examples of designed proteins, where dynamics were not explicitly accounted for in the design process, whose coordinated motions or active site dynamics, as observed by MD simulation, enhanced or detracted from their function. Many protein functions depend on sizeable or subtle conformational changes, so we finally discuss the computational design of proteins to perform a specific function that requires consideration of motion by multi-state design.

Keywords: de novo protein design; ancestral sequence reconstruction; consensus design; fold switching; molecular dynamics.