scholarly journals Packing of apolar side chains enables accurate design of highly stable membrane proteins

Science ◽  
2019 ◽  
Vol 363 (6434) ◽  
pp. 1418-1423 ◽  
Author(s):  
Marco Mravic ◽  
Jessica L. Thomaston ◽  
Maxwell Tucker ◽  
Paige E. Solomon ◽  
Lijun Liu ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Hydrophobic Effect ◽  
Side Chain ◽  
Side Chains ◽  
Chain Packing ◽  
Membrane Protein Folding ◽  
Natural Protein ◽  
Accurate Design ◽  
Polar Interactions ◽  
Packing Code

The features that stabilize the structures of membrane proteins remain poorly understood. Polar interactions contribute modestly, and the hydrophobic effect contributes little to the energetics of apolar side-chain packing in membranes. Disruption of steric packing can destabilize the native folds of membrane proteins, but is packing alone sufficient to drive folding in lipids? If so, then membrane proteins stabilized by this feature should be readily designed and structurally characterized—yet this has not been achieved. Through simulation of the natural protein phospholamban and redesign of variants, we define a steric packing code underlying its assembly. Synthetic membrane proteins designed using this code and stabilized entirely by apolar side chains conform to the intended fold. Although highly stable, the steric complementarity required for their folding is surprisingly stringent. Structural informatics shows that the designed packing motif recurs across the proteome, emphasizing a prominent role for precise apolar packing in membrane protein folding, stabilization, and evolution.

scholarly journals Local Bilayer Hydrophobicity Modulates Membrane Protein Stability

2020 ◽  
Author(s):  
Dagan C. Marx ◽  
Karen G. Fleming
Keyword(s):  
Protein Folding ◽  
Membrane Protein ◽  
Hydrophobic Effect ◽  
Water Concentration ◽  
Side Chain ◽  
Interfacial Region ◽  
Side Chains ◽  
Free Energies ◽  
Membrane Protein Folding ◽  
And Function

ABSTRACTThrough the insertion of nonpolar side chains into the bilayer, the hydrophobic effect has long been accepted as a driving force for membrane protein folding. However, how the changing chemical composition of the bilayer affects the magnitude side chain transfer free energies has historically not been well understood. A particularly challenging region for experimental interrogation is the bilayer interfacial region that is characterized by a steep polarity gradient. In this study we have determined the for nonpolar side chains as a function of bilayer position using a combination of experiment and simulation. We discovered an empirical correlation between the surface area of nonpolar side chain, the transfer free energies, and the local water concentration in the membrane that allows for to be accurately estimated at any location in the bilayer. Using these water-to-bilayer values, we calculated the interface-to-bilayer transfer free energy . We find that the are similar to the “biological”, translocon-based transfer free energies, indicating that the translocon energetically mimics the bilayer interface. Together these findings can be applied to increase the accuracy of computational workflows used to identify and design membrane proteins, as well as bring greater insight into our understanding of how disease-causing mutations affect membrane protein folding and function.

scholarly journals Too packed to change: site-specific substitution rates and side-chain packing in protein evolution

2014 ◽  
Author(s):  
María Laura Marcos ◽  
Julian Echave
Keyword(s):  
Protein Evolution ◽  
Packing Density ◽  
Main Chain ◽  
Side Chain ◽  
Side Chains ◽  
Contact Density ◽  
Chain Packing ◽  
Site Specific ◽  
Stress Theory ◽  
Side Chain Packing

In protein evolution, due to functional and biophysical constraints, the rates of amino acid substitution differ from site to site. Among the best predictors of site-specific rates is packing density. The packing density measure that best correlates with rates is the weighted contact number (WCN), the sum of inverse square distances between the site’s Cαand the other Cαs . According to a mechanistic stress model proposed recently, rates are determined by packing because mutating packed sites stresses and destabilizes the protein’s active conformation. While WCN is a measure of Cαpacking, mutations replace side chains, which prompted us to consider whether a site’s evolutionary divergence is constrained by main-chain packing or side-chain packing. To address this issue, we extended the stress theory to model side chains explicitly. The theory predicts that rates should depend solely on side-chain packing. We tested these predictions on a data set of structurally and functionally diverse monomeric enzymes. We found that, on average, side-chain contact density (WCNρ) explains 39.1% of among-sites rate variation, larger than main-chain contact density (WCNα) which explains 32.1%. More importantly, the independent contribution of WCNαis only 0.7%. Thus, as predicted by the stress theory, site-specific evolutionary rates are determined by side-chain packing.

scholarly journals Membrane Proteins Have Distinct Fast Internal Motion and Residual Conformational Entropy

2020 ◽  
Author(s):  
Evan S. O’Brien ◽  
Brian Fuglestad ◽  
Henry J. Lessen ◽  
Matthew A. Stetz ◽  
Danny W. Lin ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Lipid Bilayers ◽  
Transmembrane Helix ◽  
Water Soluble ◽  
Side Chain ◽  
Side Chains ◽  
Amino Acid Side Chain ◽  
Relaxation Techniques ◽  
Conformational Entropy ◽  
Large Reservoir

AbstractFor a variety of reasons, the internal motions of integral membrane proteins have largely eluded comprehensive experiential characterization. Here, the fast side chain dynamics of the 7-transmembrane helix protein sensory rhodopsin II and the beta-barrel bacterial outer membrane channel protein W have been characterized in lipid bilayers and detergent micelles by solution NMR relaxation techniques. Though of quite different topologies, both proteins are found to have a similar and striking distribution of methyl-bearing amino acid side chain motion that is independent of membrane mimetic. The methyl-bearing side chains of both proteins, on average, are more dynamic in the ps-ns time regime than any soluble protein characterized to date. Approximately one third of methyl-bearing side chains exhibit extreme rotameric averaging on this timescale. Accordingly, both proteins retain an extraordinary residual conformational entropy in the folded state, which provides a counterbalance to the absence of the hydrophobic effect that normally stabilizes the folded state of water-soluble proteins. Furthermore, the large reservoir of conformational entropy that is observed provides the potential to greatly influence the thermodynamics underlying a plethora of membrane protein functions including ligand binding, allostery and signaling.

Influence of Flexible Side-Chains on the Breathing Phase Transition of Pillared Layer MOFs: A Force Field Investigation

2020 ◽  
Author(s):  
Julian Keupp ◽  
Johannes P. Dürholt ◽  
Rochus Schmid
Keyword(s):  
First Principles ◽  
Good Accuracy ◽  
Field Investigation ◽  
Square Lattice ◽  
Side Chain ◽  
Second Step ◽  
Side Chains ◽  
Dynamics Simulations ◽  
Complex Phenomena ◽  
Closed Pore

The prototypical pillared layer MOFs, formed by a square lattice of paddle-<br>wheel units and connected by dinitrogen pillars, can undergo a breathing phase<br>transition by a “wine-rack” type motion of the square lattice. We studied this not<br>yet fully understood behavior using an accurate first principles parameterized force<br>field (MOF-FF) for larger nanocrystallites on the example of Zn 2 (bdc) 2 (dabco) [bdc:<br>benzenedicarboxylate, dabco: (1,4-diazabicyclo[2.2.2]octane)] and found clear indi-<br>cations for an interface between a closed and an open pore phase traveling through<br>the system during the phase transformation [Adv. Theory Simul. 2019, 2, 11]. In<br>conventional simulations in small supercells this mechanism is prevented by periodic<br>boundary conditions (PBC), enforcing a synchronous transformation of the entire<br>crystal. Here, we extend this investigation to pillared layer MOFs with flexible<br>side-chains, attached to the linker. Such functionalized (fu-)MOFs are experimen-<br>tally known to have different properties with the side-chains acting as fixed guest<br>molecules. First, in order to extend the parameterization for such flexible groups,<br>1a new parametrization strategy for MOF-FF had to be developed, using a multi-<br>structure force based fit method. The resulting parametrization for a library of<br>fu-MOFs is then validated with respect to a set of reference systems and shows very<br>good accuracy. In the second step, a series of fu-MOFs with increasing side-chain<br>length is studied with respect to the influence of the side-chains on the breathing<br>behavior. For small supercells in PBC a systematic trend of the closed pore volume<br>with the chain length is observed. However, for a nanocrystallite model a distinct<br>interface between a closed and an open pore phase is visible only for the short chain<br>length, whereas for longer chains the interface broadens and a nearly concerted trans-<br>formation is observed. Only by molecular dynamics simulations using accurate force<br>fields such complex phenomena can be studied on a molecular level.

Polypeptides Folding: Rules for the Calculation of the Backbone Dihedral Angles φ starting from the Amino Acid Sequence

2020 ◽  
Author(s):  
Michele Larocca
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Theoretical Approach ◽  
Polypeptide Chain ◽  
Hydrophobic Effect ◽  
Side Chain ◽  
Dihedral Angles ◽  
Mechanical Forces ◽  
Specific Chemical

<p>Protein folding is strictly related to the determination of the backbone dihedral angles and depends on the information contained in the amino acid sequence as well as on the hydrophobic effect. To date, the type of information embedded in the amino acid sequence has not yet been revealed. The present study deals with these problematics and aims to furnish a possible explanation of the information contained in the amino acid sequence, showing and reporting rules to calculate the backbone dihedral angles φ. The study is based on the development of mechanical forces once specific chemical interactions are established among the side chain of the residues in a polypeptide chain. It aims to furnish a theoretical approach to predict backbone dihedral angles which, in the future, may be applied to computational developments focused on the prediction of polypeptide structures.</p>

scholarly journals Effects of Amino Acid Side-Chain Length and Chemical Structure on Anionic Polyglutamic and Polyaspartic Acid Cellulose-Based Polyelectrolyte Brushes

Polymers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1789
Author(s):  
Dmitry Tolmachev ◽  
George Mamistvalov ◽  
Natalia Lukasheva ◽  
Sergey Larin ◽  
Mikko Karttunen
Keyword(s):  
Glutamic Acid ◽  
Chain Length ◽  
Chemical Structure ◽  
Side Chain ◽  
Side Chains ◽  
Side Chain Length ◽  
Polyelectrolyte Brushes ◽  
Grafting Density ◽  
The Difference ◽  
Cellulose Surface

We used atomistic molecular dynamics (MD) simulations to study polyelectrolyte brushes based on anionic α,L-glutamic acid and α,L-aspartic acid grafted on cellulose in the presence of divalent CaCl2 salt at different concentrations. The motivation is to search for ways to control properties such as sorption capacity and the structural response of the brush to multivalent salts. For this detailed understanding of the role of side-chain length, the chemical structure and their interplay are required. It was found that in the case of glutamic acid oligomers, the longer side chains facilitate attractive interactions with the cellulose surface, which forces the grafted chains to lie down on the surface. The additional methylene group in the side chain enables side-chain rotation, enhancing this effect. On the other hand, the shorter and more restricted side chains of aspartic acid oligomers prevent attractive interactions to a large degree and push the grafted chains away from the surface. The difference in side-chain length also leads to differences in other properties of the brush in divalent salt solutions. At a low grafting density, the longer side chains of glutamic acid allow the adsorbed cations to be spatially distributed inside the brush resulting in a charge inversion. With an increase in grafting density, the difference in the total charge of the aspartic and glutamine brushes disappears, but new structural features appear. The longer sides allow for ion bridging between the grafted chains and the cellulose surface without a significant change in main-chain conformation. This leads to the brush structure being less sensitive to changes in salt concentration.

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