Proteins & Molecular Dynamics

1. Proteins & Molecular Dynamics Sajal Dash

2. Overview 1. Protein Structure and Protein Folding 2. Protein Crystallography 3. Molecular Dynamics Simulation

3. 1. Protein Structure and Folding

4. Atom Everything is made of atom Three particles- neutron, proton, electron

5. Molecules One or more atoms join together by forming bonds to form a molecule

6. Amino Acid Amino acids are critical to life, and have many functions in metabolism One particularly important function is to serve as the building blocks of proteins

7. Amino Acids(Contd) In solution it has two forms Un-Ionized Zwitterion

8. From Amino Acid to Proteins A peptide bond (amide bond) is a covalent chemical bond formed between two molecules when the carboxyl group of one molecule reacts with the amine group of the other molecule, thereby releasing a molecule of water (H2O).

9. From Amino Acid to Proteins

10. Backbone of the Polymer Properties of a polypeptide chain arise from the nature of its backbone Distinctive feature is an amide link -CO-NH-

11. Degrees of Freedom Given peptide bond is planar, polypeptide chain has two degrees of freedom per residue

12. Helix Structure Change the phi and psi angles to create twisted structures Hydrogen Bond and disulfide bond help to stabilize the structure If the twist at every alpha carbon are the same, then the chain falls naturally into a helix

13. Protein Structure Hierarchy Primary Structure: The order/ number of amino acids in a polypeptide chain. This forms a -N-C-C-N-C-C-N-C-C- backbone to the molecules

14. Secondary Structure: The primary structure of a polypeptide has group projecting from the N-C-C backbone. These groups can attract each other and through hydrogen bonding cause a folding of the amino acid chain. Three noted forms: Alpha Helix Beta-pleated sheet Open Loops

15. Alpha Helix α-helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier

16. Beta Sheets The β sheet (also β-pleated sheet) is the second form of regular secondary structure in proteins, only somewhat less common than alpha helix Consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet

17. Beta Sheets

18. Tertiary Structure Tertiary structure is the three-dimensional conformation of a polypeptide. In other words there are folds in a polypeptide chain.

19. Quaternary Structure: A number of tertiary polypeptides joined together

20. How Structures Are Formed http://www.youtube.com/watch?v=lijQ3a8yUYQ

21. Protein Folding Protein folding is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil. Each protein exists as an unfolded polypeptide or random coil when translated from a sequence of mRNA to a linear chain of amino acids Amino acids interact with each other to produce a well-defined three-dimensional structure, the folded protein

22. Protein Folding Failure to fold into the intended shape usually produces inactive proteins with different properties including toxic prions The amino-acid sequence (or primary structure) of a protein determines its native conformation A protein molecule folds spontaneously during or after biosynthesis the process also depends on the solvent (water or lipid bilayer),the concentration of salts, the temperature, and the presence of molecular chaperones.

23. 2. Protein Crystallography

24. X-Ray Crystallography A method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and diffracts into many specific directions From the angles and intensities of these diffracted beams, a crystallographer can produce a three-dimensional picture of the density of electrons within the crystal From this electron density, the mean positions of the atoms in the crystal can be determined, as well as their chemical bonds, their disorder and various other information

25. X-Ray Crystallography X-Ray Analysis of Crystals

26. X-Ray Crystallography Single-crystal X-ray diffraction A beam of X-rays strikes a single crystal, producing scattered beams When they land on a piece of film or other detector, these beams make a diffraction pattern of spots Strengths and angles of these beams are recorded as the crystal is gradually rotated. X-ray diffraction data can determine the mean chemical bond lengths and angles to within a few thousandths of an Ångström and to within a few tenths of a degree

27. X-Ray Crystallography Procedure: First: obtain an adequate crystal of the material under study. The crystal should be sufficiently large, pure in composition and regular in structure Second: the crystal is placed in an intense beam of X-rays, producing the regular pattern of reflections. As the crystal is gradually rotated, previous reflections disappear and new ones appear; the intensity of every spot is recorded at every orientation of the crystal

28. X-Ray Crystallography • Third: these data are combined computationally with complementary chemical information to produce and refine a model of the arrangement of atoms within the crystal. • The final, refined model of the atomic arrangement — now called a crystal structure — is usually stored in a public database

29. X-Ray Crystallography

30. 3. Molecular Dynamics

31. Molecular Dynamics Form of computer simulation in which atoms and molecules are allowed to interact for a period of time by approximations of known physics, giving a view of the motion of the particles. A specialized discipline of molecular modeling and computer simulation based on statistical mechanics

32. Challenges long MD simulations are mathematically ill-conditioned, generating cumulative errors in numerical integration that can be minimized with proper selection of algorithms and parameters. MD simulation circumvents the analytical intractability by using numerical methods

33. Its laws and theories stem from mathematics, physics, and chemistry, and it employs algorithms from computer science and information theory

34. Areas of Application In applied mathematics and theoretical physics, molecular dynamics is a part of the research realm of dynamical systems, ergodic theory and statistical mechanics in genera MD also gained popularity in materials science, biochemistry and biophysics

35. Design Constraints Simulation size (n=number of particles), time-step and total time duration must be selected so that the calculation can finish within a reasonable time period To make statistically valid conclusions from the simulations, the time span simulated should match the kinetics of the natural process

36. Design Constraints During a classical MD simulation, the most CPU intensive task is the evaluation of the potential (force field) as a function of the particles' internal coordinates common molecular dynamics simulations scale by O(n2) if all pair-wise electrostatic and van der Waals interactions must be accounted for explicitly

37. Design Constraints Running time can be reduced using Particle Mesh Ewald ( O(nlog(n)) ), P3M or good spherical cutoff techniques ( O(n) ) The time-step must be chosen small enough to avoid discretization errors (i.e. smaller than the fastest vibrational frequency in the system)

38. Microcanonical ensemble system is isolated from changes in moles (N), volume (V) and energy (E) It corresponds to an adiabatic process with no heat exchange trajectory may be seen as an exchange of potential and kinetic energy, with total energy being conserved

39. Microcanonical ensemble the following pair of first order differential equations may be written in Newton's notation as The potential energy function U(X) of the system is a function of the particle coordinates X. It is referred to "potential" in Physics, or the "force field" in Chemistry

40. Microcanonical ensemble For every timestep, each particle's position X and velocity V may be integrated with a symplectic method such as Verlet. The time evolution of X and V is called a trajectory

41. Canonical ensemble Moles (N), volume (V) and temperature (T) are conserved It is also sometimes called constant temperature molecular dynamics (CTMD) the energy of endothermic and exothermic processes is exchanged with a thermostat

42. Potentials A molecular dynamics simulation requires the definition of a potential function, or a description of the terms by which the particles in the simulation will interact The reduction from a fully quantum description to a classical potential entails two main approximations.

43. Potentials The first one is the Born-Oppenheimer approximation, which states that the dynamics of electrons are so fast that they can be considered to react instantaneously to the motion of their nuclei The second one treats the nuclei, which are much heavier than electrons, as point particles that follow classical Newtonian dynamics

44. Potentials In classical molecular dynamics the effect of the electrons is approximated as a single potential energy surface, usually representing the ground state When finer levels of detail are required, potentials based on quantum mechanics are used

45. Empirical potentials Most force fields in chemistry are empirical and consist of a summation of bonded forces associated with chemical bonds, bond angles, and bond dihedrals, and non-bonded forces associated with van der Waals forces and electrostatic charge.

46. Pair potentials vs. many-body potentials Pair Potential In many-body potentials, the potential energy includes the effects of three or more particles interacting with each other

47. Thank You!