Constant-pH Brownian Dynamics Simulations of a Protein near a Charged Surface.

Jan M. Antosiewicz,Maciej Długosz

doi:10.1021/acsomega.0c04817

Abstract

We have developed a rigid-body Brownian dynamics algorithm that allows for simulations of a globular protein suspended in an ionic solution confined by a charged planar boundary, with an explicit treatment of pH-dependent protein protonation equilibria and their couplings to the electrostatic potential of the plane. Electrostatic interactions are described within a framework of the continuum Poisson-Boltzmann model, whereas protein-plane hydrodynamic interactions are evaluated based on analytical expressions for the position- and orientation-dependent near-wall friction tensor of a spheroid. The algorithm was applied to simulate near-surface diffusion of lysozyme in solutions having pH in the range 4–10 and ionic strengths of 10 and 150 mM. As a reference, we performed Brownian dynamics simulations in which the protein is assigned a fixed, most probable protonation state, appropriate for given solution conditions and unaffected by the presence of the charged plane, and Brownian dynamics simulations in which the protein probes possible protonation states with the pH-dependent probability, but these variations are not coupled to the electric field generated by the boundary. We show that electrostatic interactions with the negatively charged plane substantially modify probabilities of different protonation states of lysozyme and shift protonation equilibria of both acidic and basic amino acid side chains toward higher pH values. Consequently, equilibrium energy distributions, equilibrium position-orientation distributions, and functions that characterize rotational dynamics, which for a protein with multiple ionization sites, such as lysozyme, in the presence of a charged obstacle are pH-dependent, are significantly affected by the approach taken to incorporate the solution pH into simulations.

Highlights

The issues that we tackle in this paper are the following: how does the solution pH affect electrostatic interactions of proteins with charged surfaces and near-surface diffusional dynamics of proteins, and what are the possible consequences of neglecting pH-dependent protonation equilibria in computational algorithms that are being applied to study protein-surface systems
In constant-pH Brownian dynamics simulations, the protein, treated as a rigid body, undergoes translational and rotational diffusion and concurrently probes different protonation states, with the probability that depends on the solution pH and, as protonation equilibria are coupled to the external electrostatic potential, on the position and orientation of the protein relative to the charged plane
Our aim here was to answer two questions: the first, how does the solution pH affect electrostatic interactions of proteins with charged surfaces and near-surface diffusive dynamics of proteins, and the second, what are the possible consequences of neglecting pH-dependent protonation equilibria in computational algorithms that are being applied to study protein-surface systems

Summary

INTRODUCTION

Interactions of proteins with charged surfaces and diffusion of proteins in electric fields are important in many applications, such as the chromatographic separation of proteins,[1] protein immobilization,[2] biosensing,[3] design of biocompatible materials for medical applications,[4] and removal of protein fouling from metal surfaces in the food and pharmaceutical industries.[5]. The issues that we tackle in this paper are the following: how does the solution pH affect electrostatic interactions of proteins with charged surfaces and near-surface diffusional dynamics of proteins, and what are the possible consequences of neglecting pH-dependent protonation equilibria in computational algorithms that are being applied to study protein-surface systems. To answer these questions, we have developed a rigid-body constant-pH Brownian dynamics (cpH BD) algorithm, which allows us to investigate effects of solution pH on diffusive dynamics of globular proteins near charged planar surfaces. What follows is the analysis and discussion of results of these three approaches to model pH effects in BD simulations of protein-surface systems, preceded by the presentation of the constant-pH BD algorithm

THEORY AND METHODS

RESULTS AND DISCUSSION

CONCLUSIONS

■ REFERENCES