COMPUTATIONAL MODELING AND NANOTECHNOLOGY FOR INVESTIGATING AND IMPROVING CARDIAC CELL FUNCTION
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1 COMPUTATIONAL MODELING AND NANOTECHNOLOGY FOR INVESTIGATING AND IMPROVING CARDIAC CELL FUNCTION L. T Al-Kury Faculty of Pharmacy and Health Science, Ajman University, P.O.Box 5102, Abu-Dhabi, U.A.E I. Haq Department of Computer Science and Computer Engineering, Ajman University, P.O.Box 5102, Abu-Dhabi, U.A.E lina_kury@yahoo.com, ihaq27@hotmail.com ABSTRACT Computer modeling and simulations play a very crucial role in understanding biological processes and systems. More powerful algorithms and faster computers are increasingly providing solutions to problems that were once unattainable. One active area of research is to investigate how proteins fold into their native state or undergo reversible conformational changes. Proper folding of a protein places a prominent role in determining its function. However, in cases where a protein misfolds, this can lead to various types of physiological disorders and diseases. In the heart, such conditions may develop into severe cardiomayopathies. Our focus here is on Phospholamban (PLB), a regulatory protein in the cardiac sarcoplasmic reticulum (SR) membrane. Using a 2-D computer model we have simulated the conformational changes in a simple dipeptide amino acid sequence. Similar mechanism is believed to be responsible for the reversible conformational changes in PLB. Furthermore, we have investigated the effect of PLB mutation on the uptake of calcium ions by Sarco/Endoplasmic Reticulum ATPase pump (SERCA2a). We propose the use of specific protein-coated nanoparticles (PCN) to target and breakdown amyloid fibrils accumulated in cardiac tissue. By investigating the physiological processes underlying cardiac disorders, this will provide clues toward understanding and curing many heart diseases. Keywords: Computer modeling, simulation, protein folding, cardiomayopathies, phospholamban, sarcoplasmic reticulum, SERCA2a, nanoparticles, amyloid. 1. INTRODUCTION The use of computer modeling and simulations has become an indispensable tool in engineering, business, mathematics and biological sciences [1]. In bioinformatics and biological systems, computational techniques have been deployed to understand the molecular dynamics and their interaction which may assist in elucidating various pathways leading to abnormalities [2]. Furthermore, hypothesis can be checked, corrected and revised based on simulated results and their correlation with actual data. In this paper we use computer modeling and simulation to investigate the physiological processes for understanding the mechanisms associated with cardiac disorders. PLB is a monomer integral membrane protein composed of 52 amino acids which form a pentamer within the SR membrane. The PLB monomer is composed of two distinct domains, a cytosolic domain at the amino terminus (domain-i) and a hydrophobic domain at the carboxyl terminus (domain-ii) [3]. PLB regulates the cardiac contractility via its modulation of SERCA2a activity [4]. SERCA2a is one of the SERCA known isoforms and it is expressed in the SR of the cardiac muscle as an integral membrane protein [5]. When dephosphorylated, PLB monomer inhibits SERCA2a by binding to the cytoplasmic and membrane domains of the pump, causing it to close. Phopholylation (at Ser16 and Thr17 in the cytoplasmic domain), causes the dissociation of the monomer, reversing the inhibition of SERCA2a and favoring the association of PLB monomers into pentamers [3], [4], [6]. Consequently, calcium ions are uptaken into the lumen of the SR by the activated pump accelerating myocyte relaxation [7]. Irregularity in PLB/SERCA2a interaction can prevent the normal heart contractility. Considerable evidences indicate that the presence of abnormalities in myocyte
2 calcium homeostasis is a prevalent and important cause for heart arrhythmias leading to heart failure [3], [5]. Protein folding research is an interesting field and currently important in understanding and curing many diseases such as Alzheimer's, cystic fibrosis, Mad Cow disease, Parkinson's disease and even many cancers [8], [9]. The 3-D structure of a native state of a protein determines its unique function. In some cases the protein may misfold and thus lead to characteristic changes in its behavior. Mutation in amino acid sequence is probably the most common cause of misfolding [10], [11]. There are various theoretical models and computer simulations of how certain proteins undergo reversible conformational changes or reach their final native states. At present there is still no definite consensus on how this transformation actually occurs. However, since then, numerous theoretical and experimental investigations have produced proliferous results providing incremental clues towards understanding how proteins fold and hence attain their unique functionalities [8]. The PLB/SERCA2a interaction is a reversible process and is determined by protein folding mechanisms [3]. Conformational change in PLB is a prior step to phosphorylation and activation of SERCA2a for calcium uptake. Irregularity in this process can delay the diastolic period of the heart cycle and subsequently, can initiate dilated cardiomyopathy [12], [13], [14]. This disease causes the heart to become enlarged to the point where it can no longer pump blood efficiently and often leads to bradycardia which can be life threatening. Many studies indicated the direct relation between PLB mutation and dilated cardiomyopathy [12], [13]. On the other hand, cardiomyopathies are not only restricted to misfolding occurring in PLB. Instead, deposition of abnormal protein known as amyloid in the heart tissue (cardiac amyloidosis) can also affect the heart function. Disordered amyloid aggregates into amyloid fibrils resulting in restrictive cardiomyopathy. In this disease, the heart is normal in size or only slightly enlarged, but it cannot relax normally during diastole [15]. With the advent of nanotechnology as a new investigative tool, this may offer unexplored ways of discovering and understanding cellular dynamics as well as physiological processes [2]. Nanomaterials such as nanotubes, nanoshells and nanoparticles, can be fabricated with predefined characteristics to provide biocompatible and non-biodegradable probing tools [16], [17]. 2. HYPOTHESIS In this paper, we propose three conditions leading to irregularity in heart function: (i) Hypoxia causes a decrease in ATP supply to the myocardial cells and thus hinders the phosphorylation process of PLB at Ser16 and Thr17 amino acid sequence. ATP is not only needed for phosphorylation process, but is also a requirement for the pumping activity of SERCA2a. Hypoxic conditions lead to the accumulation of calcium ions in the mitochondria which begins to swell resulting in abnormal cellular function. (ii) Mutation at the phosphorylation sites of PLB could lead to small but critical structural changes that interfere with PLB/SERCA2a coupling mechanism. Once PLB binds to SERCA2a it is unable to decouple. Although there is a normal ATP supply, a large number of SERCA2a pumps are in their inactive (closed) conformation which diminishes the uptake of calcium ions. On the other hand, if mutation in PLB occurs at SERCA2a transmembrane binding site, this will discourage the PLB/SERCA2a coupling. As a result, SERCA2a will remain active (open). (iii) The use of protein-coated nanoparticles (PCN) is suggested for the removal of amyloid deposits in cardiac tissue.
3 3. RESULTS AND DISCUSSION Figure 1 shows the distribution of electric potential (arbitrary units) in the vicinity of a linear dipeptide chain as calculated using the discretized Laplace equation [16]. In solution, the dipeptide chain is in its ionic state. The regions colored yellow and orange represent a basic and a nonpolar (hydrophobic) amino acid residue, respectively. In this simulation, we have assumed that the dipeptide bond has only one degree of freedom i.e., rotation along the C α -C (colored grey) in the the plane of the paper. S1 S3 S5 S S (a) (b) Figure 1: (a) Represents a simplified model of a dipeptide chain with a basic (yellow) and non polar (orange) amino acid residues. (b) Represents the electric potential distribution in the vicinity of the dipeptide chain. Note: Units/values of potential are arbitrary. Figure 2 shows the redistribution of electric potential in presence of two charged molecules (colored blue) that have attached to the basic residue. This results in a conformational change in which the hydrophobic residue will realign itself to be as far away as possible from the attached charged molecule. The hydrophobic end will rotate about the C α -C bond, i.e., in our results the rotation is in an anticlockwise direction. Upon the removal of the attached molecule the dipeptide chain will revert back to its original shape as expected. S1 S3 S5 S S (a) (b) Figure 2: (a) Represents two polar molecules (blue) attached to the dipeptide chain at its basic end. (b) Represents the recalculated electric potential distribution. Note: Units/values of potential are arbitrary.
4 The above mechanism is believed to occur during PLB phosphorylation and PLB/SERCA2a interaction. When calcium ion concentration in the cytosol elevates, this induces a conformational change in the PLB/SERCA2a complex. In this new configuration the phosphate binding site on the PLB is exposed. As this occurs, it destabilizes PLB/SERCA2a complex. The binding of phosphate induces a negative charge on PLB monomer and hence, is repelled away from SERCA2a. This allows SERCA2a to open and actively pump calcium ions into the lumen of the SR. Consequently, the calcium concentration in the cytosol decreases which encourages the disassociation of PLB monomers from the pentamer and the cycle is repeated. However, further work in computer modeling is required to investigate the continuously varying electric potential due to the dynamic interaction of ions and molecules under different conditions such as PH and temperature. This will provide a better understanding of the interaction between PLB and SERCA2a. Under hypoxia, PLB/SERCA2a interaction is impaired due to insufficient ATP supply. This results in significant disruption in calcium ion transients in cardiac myocytes [16], [18]. The cell undergoes anaerobic respiration to maintain normal cellular functions. However, prolonged hypoxic conditions lead to the accumulation of lactic acid in the cytosol, reducing the intracellular ph. The mitochondria deteriorate as more and more calcium accumulate [19]. The diminished uptake of calcium ions causes the disruption of the normal heart rhythm, and results in a total decrease in pumping efficiency of the heart (bradycardia). Conformational change in PLB is a prior step to phosphorylation. Mutation in PLB at the phosphorylation sites can inhibit the reversible conformational change needed for the activation of SERCA2a. The overall interruption in calcium uptake delays the diastolic period of the heart cycle and subsequently, can initiate dilated cardiomyopathy [12], [13], [14]. If mutation occurs in the transmembrane domain, this will prevent PLB/SERCA2a coupling and as a result, SERCA2a will remain in the activated configuration. The frequency of excitation of the cardiac cell will become increasingly high (tachycardia) which may develop into ventricular fibrillation. Cardiac amyloidosis is a disorder caused by the deposition of an abnormal protein (amyloid) in the heart tissue, resulting in decreased heart function. It is proposed that PCNs can be coated with a specific protein that has affinity to amyloid fibrils. Once PCNs become attached, they can start breaking down the amyloid plaque. These PCN complexes can be used to administer therapeutic drugs for targeted cardiac amyloidosis disease. CONCLUSION Computer models and simulations have been used to investigate conformational changes due to protein-protein interaction. Results have shown that improper conformational changes may hinder normal biological processes and hence give rise to various types of disorders. PLB/SERCA2a interaction was investigated to understand precursors leading to cardiomyopathies. Understanding the molecular nature of the interaction between PLB and SERCA2a as well as PLB's regulatory mechanisms is necessary to pursue these pathways in the treatment of cardiac disease. PCNs may provide better therapeutic benefit for delivering drugs locally at the site of amyloid deposition. REFERENCES [1] Sperelakis N., et al, Propagated Repolarization of Simulated Action Potentials in Cardiac Muscle and Smooth Muscle, Theor. Biol. Med. Model, 2. [2] Kury L., et al, Atherosclerosis-targeted Nanolipase Buckyballs. Proc.of the First UAE International Conference on Biological and Medical Physics, pp 171, ICBMP, [3] Paterlini M.G. and David D.T, The α-helical Propensity of the Cytoplasmic Domain of Phospholamban. A Molecular Dynamics Study of the Effect of Phosphorylation and Mutation, Biophys. J., 88, 5, 2005.
5 [4] Chen Z., et al, Spatial and Dynamic Interactions between Phospholamban and the Canine Cardiac Ca++ Pump Revealed with Use of Heterobifunctional Cross-Linking Agents, J. Biol. Chem., 278, 48, , [5] Prestle J., et al, Ca++ Handling Proteins and Heart Failure: Novel Molecular Targets, Curr. Med. Chem., 10, 11, [6] Heather K. B., et al, Phospholamban: Protein Structure, Mechanism of Action and Role in Cardiac Function, Physiol. Rev., 78, , [7] Sharma P., et al, Cytoplasmic Interactions between Phospholamban Residues 1-20 and the Calcium-Activated ATPase of the Sarcoplasmic Reticulum, Biochemical J., 335, , [8] Machaalek A., A Step Closer to Understanding Proteins Fold. National Institute of General medical Sciences, June [9] Solomovici J., et al, Conformational Diseases and the Protein Folding Problem: Role of Amino-Acid Propensity to be Embedded in Context of Specific Usage of Synonymous Codons. Genetic Code Degeneracy and Folding, Biogenic Amines, 18, 3, [10] Vang S. et al, Actin mutations in hypertrophic and dilated cardiomyopathy cause inefficient protein folding and perturbed filament formation, Eur. J. Biochem., 272, 8, 2037, 2005 [11] Chow M., et al, Polyglutamine expansion in ataxin-3 does not affect protein stability: implications for misfolding and disease, J. Biol. Chem., 279, 46, [12] Kobra H. et al, Human Phospholamban Null Results in Lethal Dilated Cardiomyopathy Revealing a Critical Difference between Mouse and Human, J. Clin. Inves., 111, , [13] Schmidt A.G., et al, Phospholamban: A Promising Therapeutic Target in Heart Failure?, Cardiovasc. Drugs Ther., 15, 5, , [14] Schmitt J. P., et al, Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban, Science, 299, 5611, , [15] Hattori T., et al. Clinical and Pathological Studies of Cardiac Amyloidosis in Transthyretin type Familial Amyloid PolyNeuropathy, Amyloid, 10, [16] Kury L. and Haq I, Simulation of Hypoxia Induced SERCA2a Pump Blockage Using Nanotubes. Proc.of the First UAE International Conference on Biological and Medical Physics, pp 162, ICBMP, [17] Ajay K. and Curtis A. Surface Modification of Superparamagnetic Iron Oxide Nanoparticles and their Intracellular Uptake, Eur. Cell. Mater., 4, 2, 101-2, [18] Chen Z., et al, Role of Leucine 31 of Phospholamban in Structural and Functional Interactions with the Ca++ Pump of Cardiac Sarcoplasmic Reticulum, J. Biol. Chem., 280, 11, , [19] Crouser E. D., et al, Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity, Crit. Care Med., 30, 2, , 2002.
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