Molecular Modelling, Dynamics, and Docking of Membrane Proteins: Still a Challenge

Molecular Modelling, Dynamics, and Docking of Membrane Proteins: Still a Challenge

Nanda Kumar Yellapu (Vector Control Research Centre, India)
DOI: 10.4018/978-1-5225-0362-0.ch007
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Abstract

Computational tools and techniques are now most popular and promising to progress the research at rapid rate. Molecular modelling studies contribute their maximum role in wide variety of disciplines especially in proteomics and drug discovery strategies. Molecular dynamics and molecular docking algorithms are now became an essential part in daily research activities of every laboratory throughout the world. These strategies are now well established and standardised to study any specific protein of interest and drug molecule. But still there exist considerable drawbacks in a special concern with membrane proteins as the presently available tools and methods cannot be applied directly to them. Modelling, dynamics and docking studies of membrane proteins need a special care and attention as several challenges are to be crossed with an intensive care to produce a reliable result. This chapter is aimed to discuss such challenges and solutions to handle membrane proteins.
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Introduction

Membrane Proteins

Cell membranes are the most indispensable attributes of any living organisms that safeguard the integrity of a cell by wrapping around. It acts as a potential barrier to perform several physiological functions by offering complex molecular machineries. These multifarious functions and mechanisms of membranes are facilitated and regulated by an inimitable group of proteins called as membrane proteins which are of both surface and integral types (Figure 1). They play a vital role as channels for the transport of ions and molecule to meet the regular demands of biochemical functions (Cooper, 2000).

Figure 1.

Membrane and membrane proteins; their significant role as transporters and signal transducers

The structural and functional characterization of membrane proteins is typically a thorny task as the difficulties are associated with providing membrane environment that limits the purification and crystallization. Recent advancement in the technologies has led to the structural and functional characterization of several membrane proteins by providing their experimental structural information (Tatulian, 2000). But still it is not meeting the required demand as presently only 2% of membrane protein structures were solved. Such demanding situations paved a spectacular way for the construction of membrane protein models through computational modelling methods (Arinaminpathy et al., 2009). There exist very narrow traditions to construct the protein models but providing an immense support to the structural biologists (Lacapère et al., 2007). Such ways even relies on the experimental data of pre-existing proteins (Ash et al., 2004). Such methods are incredibly known as homology modelling methods; nevertheless homology modelling also fails many times with membrane models as the availability of experimental data for them is very limited. Construction of such models remains as a challenge when the subject of protein is very demanding and necessitous. This chapter is going to describe how such situations will overcome. Stepwise recurrent methodologies with unequivocal and particularized algorithms can be followed where the propensities of amino acids can be utilized to construct the membrane protein models where de novo modelling is one of the methods comes under this technology. Even, this also never solve the problem entirely, as this idea works out well with the small proteins and still leavening the challenge unsolved as the membrane proteins usually bigger in size. This chapter will further deals, how the larger size membrane protein models are constructed. The constructed models must represent or resemble a natural conformation so as to mimic the experimental model. How it can be made? Still another challenge remnants, whether the protein model fits into the membrane structure in line or aligns properly in the lipid bilayer. What would be thickness of the membrane for a specified protein? This chapter will explain detailed procedural solutions for all these challenges to obtain an ideal theoretical model for any membrane protein irrespective of its size.

A membrane structure with its phospholipid bilayers and component proteins resembles a disordered environment. Several types of interactions such as electrostatic, hydrophobic, covalent and hydrogen bonding etc., contribute to the dynamic moments and functions of membrane proteins. Such interactions will drive the proteins to function dynamically. Characterization and monitoring of such behaviour of channels is really challenging task through experimental techniques but can make easy by in silico means applying molecular dynamics (MD) simulation studies. Beyond the static conformation of a membrane protein, addition of membranes, orientation of model in the membrane and finally providing the membrane like environments can be done so as to mimic the in vivo environment. Simulation of such atomic models plays a vital role in shaping the perfect view to characterize the function of a membrane protein (Chang et al., 2005). Molecular dynamics simulations, irrespective of theoretical or experimental structures, offer a distinctive direction for the interpretation and correlation of structures with their function (Lindahl & Sansom, 2008). The most essential physiological functions of membrane proteins such as molecular recognition, ion regulation and energy transduction are regulated by their dynamic moments which are offered by the internal dynamic folding and orientation of several conformations of the proteins. Inspection, characterization and interpretation of such dynamic motions are highly convoluted and challenging task through experimental means and further are solved by computational simulations. Such characterizations works well with small and cytosolic proteins and when come to large and membrane proteins it will prone to several challenges. The membrane proteins will behave differently when they are present in lipid environment as they are embedded in lipid bilayer their folding is majorly influenced by the membrane. The dynamic motions of the membrane can be monitored in presence of simulated peripheral forces that duplicate some aspect of the environment, such as its voltage and surface tension. This chapter deals with the challenges associated with the membrane protein dynamics especially how the simulation of ions/molecules conductance works out which is the most challenging exertion in computational studies of membrane proteins because of the complexity of the potential energy surface, alternate hydrophilic and hydrophobic environments that finally makes the passage of ions/molecules more specific.

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