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Introduction to Biomolecular Structure and Modeling Dhananjay Bhattacharyya Biophysics Division Saha Institute of Nuclear Physics Kolkata

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Presentation on theme: "Introduction to Biomolecular Structure and Modeling Dhananjay Bhattacharyya Biophysics Division Saha Institute of Nuclear Physics Kolkata"— Presentation transcript:

1 Introduction to Biomolecular Structure and Modeling Dhananjay Bhattacharyya Biophysics Division Saha Institute of Nuclear Physics Kolkata

2 Biomolecular Structures These are determined experimentally by X-Ray Crystallography Nuclear Magnetic Resonance Spectroscopy Neutron Diffraction Study Raman Spectroscopy And also by theoretical methods

3 2d sin  =n

4 Nucleic Acid Backbone is Connected to Either of Four Different Bases

5 A G T C


7 Proteins (polymers) are made up of Amino Acids (monomer units) There are Twenty different Amino Acids with different shape, size and electrostatic properties. These amino acids form covalent bonds to form a linear polypeptide chain.

8 Alanine Phenylalanine Serine Cystine

9 Glutamic Acid (Negatively charged) Arginine (Positively charged)

10 Amino Acids are joined together by covalent bonds, called peptide bond, which is structurally very important

11  helix: Hydrogen bonding between every i  i+4 residues

12  sheet: Hydrogen bonding between i  j, i+1  j-1 (Antiparallel), or i  j, i+1  j+1 (parallel)

13 Coordinate System: External coordinates, such as (x,y,z), (r, ,  ), (r, ,z) Internal coordinates (BondLength, BondAngle, TorsionAngle)

14 Bond Length Bond Angle Torsion Angle

15 Internal  External Coordinate

16 Generated coordinates H 0.000000 0.000000 0.000000 C 0.000000 0.000000 1.089000 C 1.367073 0.000000 1.572333 C 2.050610 -1.183920 1.089000 C 3.417683 -1.183920 1.572333 H -0.513360 0.889165 1.452000 H -0.513360 -0.889165 1.452000

17  

18 Theoretical Modeling of Biomolecules:  Quantum Mechanics based Methods  Statistics based Methods  Classical or Molecular Mechanics methods

19 Peptide modeling initiated in India by G.N. Ramachandran (1950s) Postulates: Impenetrable spherical volumes for each atom Radius of the sphere depend on atom type No two atomic spheres can overlap if they are not covalently bonded  

20 Between HNOCPS H 2.0 (1.9)2.4 (2.2) 2.65(2.5) N 2.7 (2.6) 2.9 (2.8)3.2 (3.1)3.1 (3.0) O 2.7 (2.6)2.8 (2.7)3.2 (3.1)3.1 (2.9) C 3.0 (2.9)3.4 (3.2)3.3 (3.1) P 3.5 (3.3) S Normal and Extreme Limit (within parenthesis) distances (Å) used by Ramachandran co-workers

21 Original Ramachandran Plot Fully Allowed Regions Partially Allowed Regions

22 Ramachandran plot for 202 proteins at 1.5A or better resolution

23 Variation of angle by 5 o allowed to fit observed phi-psi of protein structures.

24 Schrodinger Equation: Quantum Mechanics Time dependent (3 Dimensional) Time independent

25 DFT formalism with B3LYP Pseudoeigenvalue equation: where Potential due to exchange-correlation, is defined by with a, b and c as parameters obtained from fit with experimental data for sample compounds, E x are for electron exchange and E c are for correlation. Essentials of Computational Chemistry by C.J. Cramer (2002) John Wiley & Sons Ltd,

26 Input data (atom coordinates, basis sets) Generate input guess density (overlap integrals) Construct the potential and Solve Kohn-Sham equation Generate output densities from Solutions to Kohn-Sham equations Are input and output density same? Analyze electronic population Repeat the cycle using the output density as the input density YESNO FLOW CHART DESCRIBING THE DFT METHODOLOGY

27 G:C W:W C  E = -26 kcal/mol A:U W:W C  E = -14 G:U W:W C  E = -15 A:G H:S T  E = -10 A:G s:s T  E = -6 A:U H:W T  E = -13 A:A H:H T  E = -10 G:A W:W C  E = -15 G:A S:W T  E = -11 A:A W:W T  E = -12 A:U W:W T  E = -13 A:A H:W T  E = -11 2=>NH..O 1=>NH..N 1=>NH..O 1=>NH..N 2=>NH..O 2=>NH..N 1=>NH..N 1=>CH..O 1=>NH..O 1=>NH..N 2=>NH..N 1=>NH..O 1=>NH..N 2=>NH..N 1=>NH..O 1=>NH..N 1=>NH..O 1=>NH..N Strengths of different H-bonds from 33 non-canonical Base Pairs

28 Considered Energy components, E NHO, E NHN, etc are additive. Additional stabilities,  i may come from van der Waals, dipole- dipole etc interactions. Least Squares Fit indicates  i, errors should be smallest for best Fit Type of H-bond  E (kcal/mol) N-H…O-7.82 N-H…N-5.62 O-H…N-6.89 C-H…O-1.33 C-H…N-0.67 A. Roy, M. Bhattacharyya, S. Panigrahi, D. Bhattacharyya, (2008) J. Phys. Chem. B (in press)

29 Netropsin like drugs bind in the B-DNA narrow and deep minor groove

30 Actinomycin D like drugs make their place in between two stacked base pairs by distorting the DNA double helix

31 DNA kinks by 90 o at the dyad location while binding to two subunits of Catabolite Activator Protein (CAP)

32 TATA-box binding protein transforms the interfacing DNA region to A-DNA like structure

33 DNA Smooth Curvature induced by Histone proteins in Chromatin (Nucleosome)

34 Definition and Nomenclature of Base Pair Doublet Parameters

35 Calculation of Base Pair parameters by NUPARM Local Step Parameters: Mean Local Helix Axis: Zm = Xm  Ym, where Xm = Xaxis 1 + Xaxis 2 and Ym = Yaxis 1 + Yaxis 2 M is Base Pair Center to Center Vector Tilt : 2.0 * sin -1 ( -Zm  Y1) Roll: 2.0 * sin -1 ( Zm  X1) Twist:cos -1 (( X1  Zm)  ( X2  Zm)) Shift (Dx) M  Xm Slide(Dy)M  Ym Rise(Dz) M  Zm

36 Partial list of DNA crystal structures available at bd0001 12: A C C G A C G T C G G T bd0003 12: A C C G G T A C C G G T bd0004 12: C G C G A A T T C G C G bd0006 10: G G C C A A T T G G bd0011 12: C G C A A A T A T G C G bd0014 12: C G C G A A T T C G C G bd0015 10: C C G C C G G C G G bd0017 9: C G C G C G G A G bd0018 11: G C G A A T T C G C G bd0019 12: G G C G A A T T C G C G bd0022 12: A C C G G C G C C A C A bd0023 10: C C A G T A C T G G Bd0024 10: C C G A A T G A G G


38 Average Structural Parameters from Crystal Structures Base-Pair Step Size of Database TiltRollTwistRise G:G37-0.245.8030.993.46 G:C106-0.33-5.3738.523.32 C:G1570.663.8136.263.46 A:A116-0.010.6735.923.21 A:T540.20-0.6032.763.25 T:A18-0.020.0740.393.30 A:C20-0.370.9732.733.43 C:A47-0.192.1737.753.48 A:G340.165.3431.923.44 G:A55-0.230.5238.403.14

39 DNA Bending: Experimental and Theory SequenceExperimental R L Theoretical bending (d/l) Random1.000.98 (AAANNNNNNN) n 1.230.85 (AAAANNNNNN) n 1.600.81 (AAAAANNNNN) n 2.000.74 (AAAAAANNNN) n 2.310.72 (AAAAAAAANN) n 2.210.67 (AAAAAAAAAN) n 1.730.82

40 Curved DNA models built from Crystal parameters (A 3 G 7 ) n (A 6 G 4 ) n (A 10 ) n

41  Bond Angle Deformation Deformation from equilibrium value  costs energy. Simplest form of energy penalty is: E   k  o  

42 Bonds are also stretchable but at a cost of energy Bond Breaking energy

43 Ethane (three fold symmetry) Ethiline (two fold symmetry)

44 Normal and Extreme Limiting (within parenthesis) distances (Å) used by Ramachandran co-workers Minimum Energy position: r ij o BetweenHNOCPS H2.0 (1.9)2.4 (2.2) 2.65 (2.5) N 2.7 (2.6) 2.9 (2.8)3.2 (3.1)3.1 (3.0) O 2.7 (2.6)2.8 (2.7)3.2 (3.1)3.1 (2.9) C 3.0 (2.9)3.4 (3.2)3.3 (3.1) P 3.5 (3.3) S Interaction between Instantaneous Atomic dipoles and Induced Atomic dipoles

45 Force Field for Biomolecular Simulation

46 E(  x,  y,  z) E(  x+1,  y,  z) E(  x+2,  y,  z) ….. Search for Conformation with Lowest Energy

47 Multivariable Optimization: NP-hard Problem Systematic Grid Search procedure: Impossible, large no. variables Guided Grid Search: Depends on Choice Approximate Method based on Taylor series Newton-Rhapson Method:

48 Energy Landscape of typical bio-molecules Energy Positional Variables

49 Always Accept Reject Accept Energy Uniformly generated Random numbers are used to accept if exp(-  U/kT) > random no and reject otherwise Conformation 0: Calculate energy (E i ) Alter conformation randomly Calculate energy (E i+1 ) Calculate ρ = exp(-(E i+1 -E i )/kT) If ρ > random no accept the conformation Repeat the procedure

50 Deterministic Method Molecular Dynamics Verlet Algorithm:

51 Leapfrog-Verlet Algorithm t 0 -1/2  tt 0 +1/2  tt 0 +3/2  t t 0 +5/2  t t 0 +7/2  t t0t0 t 0 +  t t 0 +2  tt 0 +3  t t 0 +4  t EEEE EEEE EEEE EEEE EEEE vvvv


53 Time scale of Vibrational Motions TypeWave no (cm -1 )Period T p (λ/c) (fs) T p /π (fs) O-H, N-H stretch3200-36009.83.1 C-H Stretch300011.13.5 O-C-O Asymm. Stretch240013.94.5 C=C, C=N stretch210015.95.1 C=O (carbonyl) stretch170019.66.2 C=C stretch H-O-H bend160020.86.4 C-N-H, H-N-H bend150022.27.1 C-N stretch (amides)125026.28.4 Water Libration (rocking)70041.713 C=C-H bending

54  Simple Pendulum Average Position of a simple pendulum 1 2 3 4 5 Period of measurement of position : ~2.3 T Recommended period of measurement ~T /10

55 Duration of Simulation Protein Folding requires 1  s to 1ms Ligand binding/dissociation requires 1  s No. of steps = 1ms /  t = 10 -3 s/10 -15 s = 10 12  Need of faster computer  Engaging several computers in parallel  Increasing  t by Shake, Rattle or Lincs algorithms

56 Softwares for Molecular Simulation Accelrys, MOE, SYBYL, TATA-BioSuite (Composite package, costly) CHARMM, AMBER (for Simulation, special Academic Price) GROMACS, NAMD (for Simulation, FREE) MOLDEN (for molecule Building, FREE) GAMESS (for QM calculation, FREE)

57 Heating phase Equilibration

58 Dickerson Dodecamer seq: d(CGCGAATTCGCG) 2

59   

60 CURVES calculated values


62 S replaces O in backbone of substituted DNA. It yields two chiral conformers of DNA – PSR and PSS. S. Mukherjee and D. Bhattacharyya (2004) Biopolymers 73, 269–282



65 PS-R PS-S Normal PO PS-R PS-S

66 Students: Dr. Debashree Bandyopadhyay Dr. Shayantani Mukherjee Dr. Kakali Sen Mr. Sudipta Samanta Partially Supported by CSIR, DBT and CAMCS (SINP) Collaborators: Dr. Rabi Majudar Dr. Samita Basu Dr. Sangam Banerjee Dr. Abhijit Mitra (IIIT, Hyderabad) Dr. N. Pradhan (NIMHANS, Bangalore)

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