Coarse-grained sequences for protein folding and design

Abstract

We present the results of sequence design on our off-lattice minimalist model in which no specification of native-state tertiary contacts is needed. We start with a sequence that adopts a target topology and build on it through sequence mutation to produce new sequences that comprise distinct members within a target fold class. In this work, we use the ␣͞␤ ubiquitin fold class and design two new sequences that, when characterized through folding simulations, reproduce the differences in folding mechanism seen experimentally for proteins L and G. The primary implication of this work is that patterning of hydrophobic and hydrophilic residues is the physical origin for the success of relative contact-order descriptions of folding, and that these physics-based potentials provide a predictive connection between free energy landscapes and amino acid sequence (the original protein folding problem). We present results of the sequence mapping from a 20-to the three-letter code for determining a sequence that folds into the WW domain topology to illustrate future extensions to protein design.A n important insight into the protein folding problem is the recognition that native-state topology often plays a dominant role in the kinetics of the folding process (1, 2). This concept implies that the subtlety of interactions among 20 different amino acids that give rise to cooperative formation of native structure through backbone hydrogen bonding and specific side-chain packing of the native-state core can often be suppressed and effectively replaced by coarse-grained descriptions that capture the overall topology and spatial distribution of local and nonlocal contacts.Minimalist proteins are coarse-grained models that use an ␣-carbon trace to represent the protein backbone in which structural details of the amino acids and aqueous solvent have been integrated out and replaced with effective bead-bead interactions. In these models, the potential energy functions for bead-bead interactions are typically Go model potentials, which require direct knowledge of native-state tertiary contacts (3). These models are particularly useful in the study of proteins for cases when sequence is unimportant relative to the effects of native-state topology for determining folding rate and mechanism.However Go bead models avoid the more difficult aspect of the protein folding problem, namely its dependence on amino acid sequence. Therefore, it is not surprising that these idealized models can lack a quantitative connection to experiment in some cases (4, 5). Physics-based models return to the original problem of confronting the complexity of amino acid sequence and corresponding interplay of physical interactions that give rise to the particulars of protein stability and kinetics and therefore do not require knowledge of native-state tertiary contacts (6-11). They are more generally applicable, especially when sequence details are equally important to topology, such as that found for two members of the ubiquitin fold class, the Ig-binding protein...

On the dynamics of molecular conformation

“…The model that we study is a simplified representation of a macromolecule, where only torsional degrees of freedom (those degrees that contribute to rotations around the backbone) are taken into account. Such models have been used, for example, for modeling of the coarse-grained dynamics of the DNA molecule (11,14) and minimalist models of protein folding (15,16). Consider a situation in which there are two backbones with side chains facing each other (see Fig.…”

Sequence periodicity and secondary structure propensity in model proteins

“…30 Both the four-helix bundle and the four b sheet bundle motifs have been successfully studied using a simplified representation of the protein chain and considering only three types of residues: H for hydrophobic, L for polar, and N for ''neutral'' groups used to build the turn regions. [31][32][33][34][35][36][37][38] In these models, the secondary structure intrinsic propensity is introduced explicitly in the force field either via a dihedral potential term or via a ''helical wheel'' potential term. In all these coarse grained models, the generic HL pattern and the ''intrinsic propensity'' potential term both favor the same secondary structure motif (a helix or b sheet), which is consistent with the target fold.…”

An implicit solvent coarse-grained lipid model with correct stress profile

“…This level of coarse-grain ͑CG͒ modeling has proved appropriate for protein folding studies, explaining why native sequences fold more rapidly and more reliably relative to poorly designed or arbitrary heteropolymer sequence, 4,5 qualitatively reproducing differences in folding kinetics of small and large proteins, 6 and have been used to clarify the role of native state topology and minimal energetic frustration in the determination of folding rate and mechanism. [7][8][9][10][11][12][13][14][15] A simplifying feature of these coarse-grained protein models has been the implicit treatment of the aqueous solvent environment, which is absorbed in the effective potentials among the bead residues, solvent frictional forces, and random collisions exerted on the moving chain described by Langevin dynamics.…”