An Analysis of Biomolecular Force Fields for Simulations of Polyglutamine in Solution

Abstract

Polyglutamine (polyQ) peptides are a useful model system for biophysical studies of protein folding and aggregation, both for their intriguing aggregation properties and their own relevance to human disease. The genetic expansion of a polyQ tract triggers the formation of amyloid aggregates associated with nine neurodegenerative diseases. Several clearly identifiable and separable factors, notably the length of the polyQ tract, influence the mechanism of aggregation, its associated kinetics, and the ensemble of structures formed. Atomistic simulations are well positioned to answer open questions regarding the thermodynamics and kinetics of polyQ folding and aggregation. The additional, explicit representation of water permits deeper investigation of the role of solvent dynamics, and it permits a direct comparison of simulation results with infrared spectroscopy experiments. The generation of meaningful simulation results hinges on satisfying two essential criteria: achieving sufficient conformational sampling to draw statistically valid conclusions, and accurately reproducing the intermolecular forces that govern system structure and dynamics. In this work, we examine the ability of 12 biomolecular force fields to reproduce the properties of a simple, 30-residue polyQ peptide (Q30) in explicit water. In addition to secondary and tertiary structure, we consider generic structural properties of polymers that provide additional dimensions for analysis of the highly degenerate disordered states of the molecule. We find that the 12 force fields produce a wide range of predictions. We identify AMBER ff99SB, AMBER ff99SB*, and OPLS-AA/L to be most suitable for studies of polyQ folding and aggregation.

Structural Ensembles of Intrinsically Disordered Proteins Depend Strongly on Force Field: A Comparison to Experiment

“…[23][24][25]27,28,42,[44][45][46] On the other hand, the accuracy of unfolded state and IDP structural ensembles obtained using several widely-used force fields has been called into question. [25][26][27]43,[46][47][48][49][50][51][52][53] Piana et al suggested that modern force fields, including Amber ff99sb*-ildn and CHARMM 22* in particular, produce IDP and unfolded state ensembles that are on average too compact. 48 It has also been suggested that Amber force fields systematically underestimate chain dimensions of IDPs and unfolded states.…”

CHARMM36m: an improved force field for folded and intrinsically disordered proteins

“…To directly compare to previous C36 results, 11 we tested C36m by simulating polyglutamine (polyQ) peptide, an IDP with relatively compact collapsed states due to the hydrogen bonding interactions between polar side chains. Similar to the C36 results, the 30-residue polyQ peptide (Q 30 ) was disordered during 98% of the simulation time.…”

An Original Monomer Sampling from a Ready‐Made Aβ42 NMR Fibril Suggests a Turn‐β‐Strand Synergetic Seeding Mechanism

“…In addition, the simulated conformations of Aβ42 peptide are also largely disturbed due to the different force fields, either implicit or explicit solvent model and distinct conditions employed. For example, previous studies had confirmed that Amber and Charmm force fields always over‐stabilize the helical structure and the Gromos ones tend to form β‐structure . Extended simulation for both systems can unify some secondary structure components but all.…”