Accounting for Protein-Solvent Contacts Facilitates Design of Nonaggregating Lattice Proteins

Abstract

The folding specificity of proteins can be simulated using simplified structural models and knowledge-based pair-potentials. However, when the same models are used to simulate systems that contain many proteins, large aggregates tend to form. In other words, these models cannot account for the fact that folded, globular proteins are soluble. Here we show that knowledge-based pair-potentials, which include explicitly calculated energy terms between the solvent and each amino acid, enable the simulation of proteins that are much less aggregation-prone in the folded state. Our analysis clarifies why including a solvent term improves the foldability. The aggregation for potentials without water is due to the unrealistically attractive interactions between polar residues, causing artificial clustering. When a water-based potential is used instead, polar residues prefer to interact with water; this leads to designed protein surfaces rich in polar residues and well-defined hydrophobic cores, as observed in real protein structures. We developed a simple knowledge-based method to calculate interactions between the solvent and amino acids. The method provides a starting point for modeling the folding and aggregation of soluble proteins. Analysis of our simple model suggests that inclusion of these solvent terms may also improve off-lattice potentials for protein simulation, design, and structure prediction.

A Coarse-Grained Approach to Protein Design: Learning from Design to Understand Folding

“…follow much better the contact profile than the profile relative to sequences designed without the solvent term (Wo.S. ), indicating that our “artificial” proteins have a hydrophobic core surrounded by hydrophilic amino acids as expected for molecules that live in aqueous solutions [36]. Finally we compared the artificial HP profiles to the average profile obtained from the Pfam alignment data (PF00542) for protein 1CTF; the curve for W.S.…”

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

“…Hall (Hall and Hirota 2009;Hall et al 2005) and Abeln and Frenkel (Abeln and Frenkel 2008;Abeln and Frenkel 2011) have examined the effect of unstructured flanking polypeptide regions on the aggregation propensity (to form both amyloid fibrillar and amorphous aggregates) of central regions. They conclude that the flanking regions have a marked propensity to prevent the central regions from aggregating; they do so by 'frustrating the encounter event' that, of course, is the crucial event in the aggregation process.…”

Introduction to Protein Structure Prediction

“…In fact, the fibrillar state is more favorable than the state of separately folded structures for several protein types. The general cellular toxicity of such aggregates, puts evolutionary pressure on avoiding structural characteristics on the surface of proteins; hence it is extremely rare to observe solvent accessible β-strand edges or large hydrophobic surface patches (Richardson and Richardson, 2002;Abeln and Frenkel, 2011). The propensity proteins have to form Amyloid fibrils is relatively easy to predict (Graña-Montes et al, 2017).…”