Life science and nanotechnology software applications L. Litov, P. Petkov, G. Vayssilov University of Sofia Outlook Physics basics Quantum simulations Molecular dynamics Examples – nanotechnology Examples – life science Summary L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Physics basics L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Physics x(t ) Newton equation d v(t ) x(t ) dt d2 F m 2 x(t ) dx Schrödinger equation Probability to find P( x, t ) = Ψ* ( x, t )Ψ( x, t ) the system in (r,t) L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Quantum simulations L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Quantum simulations Schrödinger equation Born- Oppenheimer approximation ( R , R , R ... R , r , r , r ,... r ) ( R , R , R ... R ) ( r , r , r ,.. r ) 1 2 3 N 1 2 3 n nu 1 2 3 N el 1 2 3 n Schrödinger equation for electrons el el (r1 , r2 , r3 ,...rn , R) Eel (r1 , r2 , r3 ,...rn , R) me≪ m p 2 Z I1 1 / 2 el i R r rij i I , i j I ii Schrödinger equation fore nuclei H nu nu ( R1 , R2 , R3 ....RN ) Etot nu ( R1 , R2 , R3 ....RN ) Z Z 12 I J E ( R ) nu I 2 M R I I I , J IJ L. Litov E (R ) Life science and nanotechnology software applications Sofia, 10 December 2010 Quantum simulations Hartree – Fock approximation - huge computational time Density Functional Theory (DFT) - Hohenberg-Kohn, Kohn- Sham Ground state properties of many electron system are determined by electron density Interacting electrons in static external potential non-interacting electrons in effective potential VASP, CP2K, CPMD, GAMESS, GAUSSIAN, Q-Chem L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Molecular Dynamics L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 From quantum to classic mechanics For particle with mass m in equilibrium and temperature T, the mean value of the momentum is Heisenberg uncertainty principle Follows that the width is It is possible to omit the quantum effects if the variations sx are less than some critical width defining the accuracy of our calculations.. Critical width L. Litov Моделиране на взаимодействия на биологични молекули Life science and nanotechnology software applications Sofia, 10 December 2010 Quantum – Classic mechanics • Electrons are treated by means of quantum mechanics • Hydrogen and Deuterium atoms at temperature 300 K can not be considered as a pure classical objects • Heavier atoms can be treated as classical objects (temperatures 300 K). Additional correction are introduced in order to take into account quantum effects. L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Solving the equations of motion Point in the phase space of the system Hamilton equations - Liouville operator H K V pi2 / 2mi V ( x) where i In Cartesian coordinates и L. Litov Do not commutate Life science and nanotechnology software applications Sofia, 10 December 2010 Solving the equations Time propagator One step propagator Applying on We obtain Velocity Verlet, Leap Frog algorithms L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Potential – force field Every atom should be included -chemical bonds with other atoms -long distance interactions V Vs Va Vt Vv Ve ... i Bond strength Sum over all bonds L. Litov i Bond angle Sum over all angles i Torsi on i i Van der Waals interactio ns Life science and nanotechnology software applications Coulomb interaction Sofia, 10 December 2010 Potential – force field Parameterization of chemical bonds vb r 12 kb r r0 2 va θ 12 ka θ θ0 2 vd φ kd 1 cosnφ φ0 V x1 , x2 ,, xN Vk x; pk k - Empirical parameters (pk) L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Potential – force field Parameterization of the other interactions Vlj rij Cij1 2 rij1 2 Cij 6 rij6 Vc rij qi q j 4 πε0 rij V x1 , x2 ,, xN vk x; pk k - Empirical parameters (pk) AMBER, CHARMM,GROMOS, GROMACS, LAMMPS, NAMD, VMD L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 New materials - nanothenology L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 nanothenology Two examples Interface between Pt8 cluster and Ce21O42 nanoparticle Reduction effect - generation of Ce3+ cations Effect on formation energy of oxygen vacancies VASP Hydrogen reverse spillover on zeolite-supported clusters Ab initio MD simulation of Rh4 and Ag4 clusters CP2K Georgi N. Vayssilov, P. Petkov, H. Aleksandrov (Univ. of Sofia) L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Platinum cluster on ceria nanoparticle Pt/CeO2 - the key component of the automotive catalyst Model: cluster Pt8 on Ce21O42 nanoparticle Reduction of one Ce4+ to Ce3+ in the most stable structures Pt Ce3+ Eads = -5.03 eV Ns = 4 O2- 1 Ce3+ Ce4+ L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Clusters Ce21O42 Plane-wave density-functional calculations Model clusters Ce21O42 VASP code PW91 gradient-corrected functional + U = 4 eV Plane wave basis, cutoff of 415 eV Spin-polarized calculations (where appropriate) Unit cells: 202020 Å, allowing ~10 Å vacuum between neighboring cluster images L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Platinum cluster on ceria nanoparticle Energy for formation of an O vacancy Ef is reduced in the presence of platinum: ΔEf = 0.44 eV -1/2 O2 1.67 eV -1/2 O2 1.23 eV L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Ab initio MD simulations of supported clusters Support - Zeolite MOR - total 295 atoms per unit cell a = 18.256, b = 20.534, c = 15.084 A angles = 90.0 Si/Al = 89/7 ≈ 13 Initial M-H distances: ~250, ~275, ~470 … pm Rh4 L. Litov Ag4 Life science and nanotechnology software applications Sofia, 10 December 2010 Ab initio MD simulation of Rh4 and Ag4 clusters Periodic ab initio MD simulations – CP2K DFT: PBE; BO MD and optimization PW basis, 200 eV cutoff for MD and 400 eV for geometry optimization NVT ensemble MD run: time step 1 fs; 1 frame = 10 fs; time ~20 ps T = 300 K; CSVR thermostat L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 10ps MD run: Proton transfer to Rh4 Protons to be transferred L. Litov Life science and nanotechnology software applications 23 Sofia, 10 December 2010 10ps MD run: Interaction with OH for Ag4 L. Litov Life science and nanotechnology software applications 24 Sofia, 10 December 2010 Life science L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Understanding of human interferon-gamma binding Human Interferon Gamma Active site Res 18-26 Active site Res 18-26 N-terminus N-terminus C-terminus C-terminus 122-143 L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Interferon-gamma and its alpha receptor PDB ID: 1fg9 Residues connected by H-bonds L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Gamma interferon binding Task To find a possible way to inhibit the gamma-interferon activity Block the binding sites of the gamma-interferon Find a ligand binding hIFN-g and blocking its activity Block the binding receptors (hIFNgRa) on the cell surface With mutated hIFN-g peptides, lacking biological activity With some other ligand Need to understand the mechanism of hIFN-g binding to its cell receptors L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 hIFNg + hIFNgRa in water 26 ns High performance computing, large scale simulation and drug design L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 INF-g C-terminus D1 domain (125KTGRKRKR132) D2 domain (137RGRR140) L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 INF-g C-terminus L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 hINF-g hIFNgRa interaction simulations GROMACS High performance computing, large scale simulation and drug design L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 INF-g C-terminus Heparin derived oligosaccharide Biochem J. 2004 November 15; 384(Pt 1): 93–99. NMR characterization of the interaction between the C-terminal domain of interferon-γ and heparin-derived oligosaccharides Cécile Vanhaverbeke,*1 Jean-Pierre Simorre,* Rabia Sadir,† Pierre Gans,*2 and Hugues Lortat-Jacob† PDB ID: 1hpn High performance computing, large scale simulation and drug design dp8 dp4 dp2 L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 hIFN-g and d8 High performance computing, large scale simulation and drug design L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Ribosome structure model The goal - construction and verification of a stable full atomistic computer model of the whole ribosome, which enables realistic simulations of various biochemical processes in the living cell. Stable ribosome subunits Construction of the whole ribosome including tRNA, mRNA, and a growing peptide chain Determination of the structure of the ribosome in water Investigation of the influence of the type of the cations on the stability of the whole ribosome (role of Na and Mg ions) Non trivial challenging task requiring a Petascale (~3.106 atoms) computing L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Ribosome big subunit CHARMM27 Force Field Explicit solvent MD simulation Crystallographic ions included NAMD 2.6 Time step 2.5 fs NVT Unstable structure even in about 0.5 ns long MD simulation L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Ribosome big subunit with Na+ counter ions Na+ ions added to crystallographic structure compensating the charge of phosphates Na+ L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Trajectories RMSD L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 COX inhibitors Investigation of the system – enzyme- inhibitor Cyclooxygenase (COX 1 and COX I2) – responsible for many cell processes Regulation and production of hormones Regulation of the Ca transfer Thrombosis aggregation Regulation of inflammatory processes ..etc. COX1 and COX2 bind with arachidonic acid – produces prostaglandines COX1 and COX2 are targets for all nonsteroidal anti- inflammatory drugs like aspirin, paracetamol etc. L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Docking Docking is based on: Search of the most suitable ligand orientation with respect to the receptor centre Define the binding affinity – using different scoring functions Calculation of the binding energy DOCK 6.4 Selectivity test 512 ligands There is no binding L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Arachidonic acid Arachidonic acid binding is reproduced correctly (crystallographic structure) RMSD = 1,820 Å; ECryst = 55,45 kcal/mol; ΔE = 4,2 kcal/mol; L. Litov EDock = 51,25 kcal/mo Life science and nanotechnology software applications Sofia, 10 December 2010 COX1 and COX2 inhibitors Investigation of inhibitor ligands Crystallographic orientation of some inhibitors are reproduced well Ibuprofen, Fluribiprofen etc Binding of specific COX2 inhibitors is under investigation Diclofenak, Celecoxib L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Conclusions Computer simulations: are extremely useful in the design of new materials can play significant role in the understanding of biological processes at atomic and molecular level significantly reduce time and cost of development of new drugs (in-silco drug design) Quantum calculations are extremely time consuming – require new algorithms and more powerful (super)computers. Simulations of large (milions of atoms) systems require supercomputing at Petascale level Problem with scaling – require new algorithms in order to reduce procesor communications Reach variety of software is installed on Bulgarian IBM BG/P supercomputer We are welcome to run your jobs at BG supercomputer L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Spare slides L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Algorithms for solving the equation of motion Error at every step Accumulated error L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Systematic errors Force field (Gromacs, NAMD) Water model – different for NAMD and GROMACS Box size Periodic boundary conditions Need special investigations L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Platinum cluster on ceria nanoparticle DOS plots of bare CeO2 and Pt8/CeO2: Pt states appear in the gap between O 2p and Ce 4f “bands” EFermi CeO2 - dashed lines Pt8/CeO2 - solid lines L. Litov Pt states Life science and nanotechnology software applications 51 51 Sofia, 10 December 2010 Energies for proton transfer to Rh4 Rh4 H ERS, kJ/mol Rin(M-H), pm 1 -272 250 2 -103 275 3 20 475 Proton transfer from distant OH group is disfavored L. Litov Energies obtained after optimization of the structures with different number of transferred H Proton transfer from near OH group to the metal cluster is favored Life science and nanotechnology software applications 52 Sofia, 10 December 2010 Systematic errors - models NAMD L. Litov GROMACS Life science and nanotechnology software applications Sofia, 10 December 2010 Systematic errors – box size High performance computing, large scale simulation and drug design L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Systematic errors - PBC L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 Systematic errors - PBC High performance computing, large scale simulation and drug design L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 High performance computing, large scale simulation and drug design L.L. Litov Second Life science and nanotechnology software applications workshop Sofia, 10 December 2010 INF-g C-terminus – dp8 interaction Configuration 1 Configuration 2 T = 0 ps High performance computing, large scale simulation and drug design T = 2000 ps L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010 INF-g C-terminus – dp8 interaction High performance computing, large scale simulation and drug design L. Litov Life science and nanotechnology software applications Sofia, 10 December 2010