Protein Folding and Structure Prediction from the Ground Up: The Atomistic Associative Memory, Water Mediated, Structure and Energy Model

Abstract

The associative memory, water mediated, structure and energy model (AWSEM) is a coarse-grained force field with transferable tertiary interactions that incorporates local in sequence energetic biases using bioinformatically derived structural information about peptide fragments with locally similar sequences that we call memories. The memory information from the protein data bank (PDB) database guides proper protein folding. The structural information about available sequences in the database varies in quality and can sometimes lead to frustrated free energy landscapes locally. One way out of this difficulty is to construct the input fragment memory information from all-atom simulations of portions of the complete polypeptide chain. In this paper, we investigate this approach first put forward by Kwac and Wolynes in a more complete way by studying the structure prediction capabilities of this approach for six α-helical proteins. This scheme which we call the atomistic associative memory, water mediated, structure and energy model (AAWSEM) amounts to an ab initio protein structure prediction method that starts from the ground up without using bioinformatic input. The free energy profiles from AAWSEM show that atomistic fragment memories are sufficient to guide the correct folding when tertiary forces are included. AAWSEM combines the efficiency of coarse-grained simulations on the full protein level with the local structural accuracy achievable from all-atom simulations of only parts of a large protein. The results suggest that a hybrid use of atomistic fragment memory and database memory in structural predictions may well be optimal for many practical applications.

Figure 1

Protocol for structural prediction using AAWSEM. The secondary structure of 1R69 is used as an illustration.

Figure 2

Maximum Q score versus sequence length for the “atomistic fragment memory” AWSEM (blue squares) and “no fragment memory” AWSEM (red circles). Maximum Q score for “homologues excluded” “database fragment memory” AWSEM (yellow diamonds) are also shown where available.

Figure 3

Prediction quality for 1R69 (a), 3ICB (b), 1N2X (c), 4CPV (d), 1MBA (e) and 2EB9 (f). Red diamonds correspond to “atomistic fragment memory” predictions, blue diamonds to “no fragment memory” predictions. In each case, 20 results from annealing simulations are shown in ascending order.

Figure 4

Alignments between structures obtained from “atomistic fragment memory” predictions shown in red, while the crystal structure is shown in white.

Figure 5

The apomyoglobin could fold properly. (A): The crystal structure of myoglobin with multiple α-helices colored from blue at the N-terminal to yellow at the C-terminal. The heme is also shown in red sticks attached to His95 on myoglobin. (B): Comparative contact maps of the maximum Q score structures obtained from “atomistic fragment memory” predictions for 1MBA and (C) 2EB8, the blue stands for contact maps for predicted structures and the red stands for native structures. The residues that are highlighted in red in the sidebars make contacts with the heme cofactor. We see that in 1MBA one of the contacting regions, the one near residue 40, makes non-native contacts with the region between 120 and 145.

Figure 6

The atomistic fragment memories guide the folding of 1R69 towards a native-like state. (A): The total potential energy decreases as Q increases. (B): Free energy profiles of 1R69 as a function of Q using atomistic fragment memory (cyan) and without fragment memory (blue). (C): The fragment memory energy (Eq. (4)) decreases as Q increases. (D): Free energy profiles are shown of the segments as a function of the Q of the individual segments (red to blue) and the global Q (yellow) are shown.