Upside: A New Dynamics Method Capable of Cooperative De Novo Protein Folding in CPU-Hours

Abstract

Protein dynamics can be simulated at many levels of resolution, from every atom to single beads representing one residue. Using only the backbone N, Cα, and C atoms, we have developed a coarse-grained model for Langevin dynamics (LD) simulations that is capable of cooperatively folding some small proteins with near A accuracy in hours on a home computer. Its extreme speed and high accuracy, respectively, are largely due to representing each residue with only the three backbone atoms but using their positions to reconstruct the influence of the missing groups. More specifically, the location of the backbone atoms defines the positions of pendant groups not explicitly represented in the model, thereby enabling the computation of the forces on these inferred positions and the distribution of these forces back onto the backbone atoms. Importantly, the reconstructed protein is associated with detailed AA- and neighbor-dependent Ramachandran maps, backbone H-bonding, and side chain packing potentials, features absent in many coarse grained folding models. This reconstruction allows the forces from a much more detailed model to act directly on the fundamental backbone degrees of freedom despite using only 3 explicit atoms per AA. This algorithm is implemented in a novel simulation framework, Upside, that is highly configurable and efficient. While Upside is originally designed to describe protein folding, we are also applying it to study intrinsically disordered and membrane proteins, as well as conformational change. Upside's extreme speed makes it an extremely powerful method for studies requiring extensive conformational sampling, for example, providing initial transition paths that can be further investigated using all-atom simulations.