Routine Access to Millisecond Time Scale Events with Accelerated Molecular Dynamics

Abstract

In this work, we critically assess the ability of the all-atom enhanced sampling method accelerated molecular dynamics (aMD) to investigate conformational changes in proteins that typically occur on the millisecond time scale. We combine aMD with the inherent power of graphics processor units (GPUs) and apply the implementation to the bovine pancreatic trypsin inhibitor (BPTI). A 500 ns aMD simulation is compared to a previous millisecond unbiased brute force MD simulation carried out on BPTI, showing that the same conformational space is sampled by both approaches. To our knowledge, this represents the first implementation of aMD on GPUs and also the longest aMD simulation of a biomolecule run to date. Our implementation is available to the community in the latest release of the Amber software suite (v12), providing routine access to millisecond events sampled from dynamics simulations using off the shelf hardware.

Figure 1

RMSD of the aMD trajectory from the crystal structure. Red, blue, green, purple, and black colors correspond to the kinetic clusters identified in the 1 ms cMD BPTI simulation. For each frame, we identify what cluster we are closest to and color it accordingly. Only a handful of transitions to the green state were observed, and we highlight them with diamond markers.

Figure 2

The free energy principal component projection of (a) 1 ms simulation, (b) 500 ns cMD ff99SB-I simulation, and (c) 500 ns aMD ff99SB-I simulation onto (PC1, PC2) defined by the 1 ms simulation. The long-lived structures are projected onto the free energy surface and are labeled as red, blue, green, purple, and black triangles. The crystal structure, 5PTI, is demarked by the red diamond (see also Movies S1 and S2).

Figure 3

The χ₁–C14 vs χ₁–C38 dihedral angle free energy surfaces of (a) 1 ms cMD simulation, (b) 500 ns cMD ff99SB-I simulation, and (c) 500 ns aMD ff99SB-I simulation. The long-lived stable states are plotted onto the free energy surface and are labeled as red, blue, green, purple, and black triangles. The crystal structure, 5PTI, is demarked by the red diamond. The major state M is labeled along with the minor states m_C14 and m_C38.