Anisotropic Protein Interactions in Salt Solutions and at Interfaces: Coarse Grained Modeling

Abstract

Anisotropic protein interactions have a strong orientation dependence resulting from an uneven distribution of charged and hydrophobic residues on the protein surface. They play an important role in protein behaviors such as protein association, surface adsorption and phase separation. In this thesis, we have studied the effect of anisotropic interactions on the behavior of various proteins mainly by focusing on electrostatic interactions. We have developed coarse grained models, specific to each system by considering their essential details and used Metropolis Monte Carlo method to simulate protein behaviors in salt solutions and at charged interfaces. We show that anisotropic dipolar interactions may overcome the net charge repulsion between similarly charged proteins and favor the protein association. The strong directionality of these interactions may reinforce specific protein orientations, required for protein activity. Note that hydrophobic anisotropy can also compete with the directionality of the dipolar interactions and may force the proteins into less favorable dipole orientations. We also show that the charge regulation effects and the specific Hofmeister ion binding can significantly alter the charge distribution of proteins, and thus they should not be overlooked in the studies of protein electrostatics. Our results indicate that to gain a comprehensive understanding of protein electrostatics, one needs to consider: (i) the higher order multipole interactions; (ii) the hydrophobic patchiness that can compete with the multipole interactions; (iii) the charge regulation effects; as well as (iv) the specific ion binding. The extent of these factors can roughly be estimated by examining the dipole moment, the locations of hydrophobic patches, the number of residues with acid dissociation constants around solution pH as well as the concentration of binding ions and the exposed area of their binding sites.

Abstract (Swedish)

Popular Abstract in English

Proteins are molecular machines of the human body which regulate all life sustaining processes such as energy production, communication, transport of essential molecules, defense against microbes, etc. They are built by small molecular units called amino acids, bound together like pearls on a necklace. Each amino acid consists of a common part and a unique side chain. The former makes up the backbone of a protein chain and the latter determines the nature of the amino acid. There are 22 kinds of amino acid side chains which provide an enormous diversity to the protein chains. The amino acid side chains can have a water- (polar) or oil-like (hydrophobic) nature. Some polar amino acids may bear a positive or negative charge depending on the environmental conditions such as acidity and salt concentration. It is a well-known phenomenon that water tends to separate from oil. This also holds for an oil-like, hydrophobic amino acid where water tends to push these amino acids together to avoid contact with them. Due to this tendency, the protein chains fold into a globular shape so that most of the hydrophobic amino acids are located in the protein interior and the polar amino acids are on the surface. However, some proteins that lack hydrophobic amino acids do not fold into a globular shape and behave as flexible chains. These proteins are called intrinsically disordered proteins.

The nature of protein interactions is determined by the distribution of charged and hydrophobic amino acids on the surface, in case of globular proteins, or in the chain, in case of disordered proteins. The segregation of positive amino acids from the negative ones results in anisotropic interactions which resemble the interactions of two magnets where opposite poles abstract and the similar ones repel each other. Thus, the nature of anisotropic interactions depends on the orientations of the proteins. These interactions can also originate from clustering of hydrophobic amino acids on protein surfaces, which creates sticky surface patches.

In this thesis, we have studied the effect of hydrophobic and charge patchiness of protein surfaces on the protein-protein and protein-surface interactions in salt solutions. We used Monte Carlo simulations to mimic protein behaviors with the help of computers and played around with the acidity and salt concentration of the protein solutions to determine their impact. We have developed system specific protein models which represent proteins by collections of interacting spheres. In the model development, we used a coarse graining approach where we have only considered the details of proteins that are essential for the specific study.

We have shown that the hydrophobic and charge patchiness on a protein surface can be altered by binding of charged salt species on the protein surface – called the Hofmeister ion effect. Under correct solution acidity, the charge residues can adapt a charged or neutral state to maximize attraction with opposite charges or to minimize repulsion with similar charges. This phenomenon is called charge regulation which can also alter the charge patchiness of the protein surfaces. The resulting complex patch interactions may reinforce specific protein orientations, and may facilitate protein associations into functional machines.

• author: Kurut Sabanoglu, Anil
• supervisor: Mikael Lund
• opponent: Dr Nielsen, Jens Erik, Senior Manager in Novozymes,Bagsvaerd Denmark
• organization: eSSENCE: The e-Science Collaboration; Computational Chemistry
• publishing date: 2014
• type: Thesis
• publication status: published
• subject: Theoretical Chemistry
• keywords: Anisotropic interactions, protein electrostatics, phase association, surface adsorption, coarse grained models, Monte Carlo simulations
• pages: 156 pages
• defense location: Getingevagen 60 Lund University, Kemicentrum, Hall B, Lund University, Lund
• defense date: 2014-09-19 13:15:00
• ISBN: 978-91-7422-365-1
• language: English
• LU publication?: yes
• additional info: The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Theoretical Chemistry (S) (011001039)
• id: 3dfc91c3-a422-48e0-818b-7f8220398707 (old id 4610736)
• date added to LUP: 2016-04-04 11:32:21
• date last changed: 2019-09-23 13:09:32