BEGIN:VCALENDAR VERSION:2.0 PRODID:-//CERN//INDICO//EN BEGIN:VEVENT SUMMARY:Development of o Hybrid Statistical Physics – Quantum Mechanical Methodology for Computer Simulations of Condensed Phases and its Implemen tation on High-Performance Computing Systems DTSTART;VALUE=DATE-TIME:20121019T090000Z DTEND;VALUE=DATE-TIME:20121019T093000Z DTSTAMP;VALUE=DATE-TIME:20261011T022906Z UID:indico-contribution-91-186@indico.ipb.ac.rs DESCRIPTION:Speakers: Ljupco Pejov (Institute of Chemistry\, Faculty of Sc ience\, Skopje\, Macedonia)\nA hybrid\, complex statistical mechanics – quantum mechanical approach which enables exact computational modeling of condensed phases at finite temperatures has been developed and implemented on high-performance computing systems. The computational approach is robu st and inherently sequential. First\, the studied physico-chemical system is modeled by a statistical physics approach\, either Monte Carlo (MC) or molecular dynamics (MD). Though in the first phase it is often sufficient to carry out a classical MC or MD simulation\, in particular cases\, when it is necessary\, one can also perform a quantum molecular dynamics simula tion (e.g. ADMP\, BOMD or CPMD). Even the classical MC/MD simulations carr ied out in the first phase can be based on interaction potentials which ha ve been derived by quantum chemical calculations. Sequentially to the firs t phase of the computation\, which actually generates either a MD trajecto ry or an appropriate sample of the system’s configurational space\, the generated trajectories are analyzed employing time-series analytic methods . In the case of e.g. MC simulations\, this is done most frequently by com putation and subsequent integration of the energy autocorrelation function \, which leads to the so-called correlation step. The last quantity is the n used to choose a representative number of configurations representing th e state of the physico-chemical system at finite temperature which will be further analyzed by a quantum mechanical approach. These\, appropriately chosen configurations for the system of interest\, are further modeled by exact quantum mechanical (QM) approach. The particular approach that needs to be implemented depends on the quantity that needs to be computed. For example\, in the case of X-H stretching vibrations\, the anharmonic X-H vi brational frequency is computed in a quantum mechanical manner with respec t to both electronic and nuclear subsystem. In this case\, first a 1D cut through the vibrational potential energy surface is computed at series of suitably generated points\, and subsequently\, the vibrational Schrodinger equation is solved either by diagonalization approach or using a variant of the discrete variable representation (DVR) methodology. As the statisti cal mechanics simulations are often done implementing periodic boundary co ndition\, the exact QM calculations in the final simulation phase are ofte n done implementing some sort of embedding of the relevant part of the sys tem. All these aspects of our developed methodology are illustrated throug h a particular example – the fluoroform solvated in liquid Kr and the no ncovalently bonded complexes which are formed between fluoroform and dimet hylether in liquid Kr. A vast variety of condensed phase systems can be tr eated by the developed approach. Achieving good parallel efficiency for ca lculations of such type is far from a trivial task without the use of high -performance low-latency MPI interconnect (such as\, e.g. a supercomputer or HPC cluster).\n\nhttps://events.saifa.rs/event/291/contributions/186/ LOCATION:National Library of Serbia URL:https://events.saifa.rs/event/291/contributions/186/ END:VEVENT BEGIN:VEVENT SUMMARY:Dynamics of uninhibited and covalently inhibited cysteine protease on non-physiological pH DTSTART;VALUE=DATE-TIME:20121019T083000Z DTEND;VALUE=DATE-TIME:20121019T090000Z DTSTAMP;VALUE=DATE-TIME:20261011T022906Z UID:indico-contribution-91-192@indico.ipb.ac.rs DESCRIPTION:Speakers: Branko J. Drakulić (Department of Chemistry-IChTM\, University of Belgrade\, Njegoševa 12\, Belgrade\, Serbia)\nCysteine pro teases involved in degradation of proteins\, widespread in plants\, parasi tes and vertebrates\, are an important medicinal chemistry target implicat ed in the diseases ranging from immunological processes to cancer. Due to conserved cysteine residue in their active site\, unsaturated ketones and their analogs represent one of the major chemotypes used for inhibitors de sign [1]. In this communication the dynamics of the papain-like cysteine p rotease isolated from the fruit\, uninhibited and inhibited with covalent inhibitor E-64 (Scheme 1)\, on non-physiological pH\, were reported mergin g results and experiences from our biochemical and medicinal chemistry lab oratories.The aim of our study is to explain some experimental findings. P roteins are modeled using similar ones with the known 3D structure\, taken from Protein Data Bank [2]. After sequence alignment residues that differ entiate templates from the experimental proteins were manually changed. Af terward the eventual existence of close contacts\, bumps or similar was ca refully checked. The protonation states of the aminoacid residues and the inhibitor ionizable groups were adjusted to pH 1.5\, using empirical funct ion [3]. Systems were neutralized with explicit counterions\, than embed i n explicit water\, obtaining the sphere having ~ 100 Å radius. Systems un der simulations were minimized during 30000 steps\, than heated to 300 K d uring 10000 steps. After equilibration\, the 5 ns unconstrained and unbias ed molecular dynamics simulation\, on 300 ± 10 K\, were performed on the each system. CHARMm22 force field and Geisteiger charges were used. Electr ostatics was treated by Particle Mesh Ewald method. The periodic boundary conditions were applied\, and 12 Å cut-off (8 Å switching)\, with pair l ist distances set to 13.5 Å. Each simulation was performed in duplicate\, using different random seeds and giving comparable results. The root-mean -square deviation of the backbone atoms and the energy profiles of the sys tems under the study proved stable\, converged simulation. The movement of the loops and the (flexible) inhibitor\, as well as radius of gyration of the selected amino-acid side chains was analyzed and conclusion derived o n the influence of the covalently bound inhibitors on the dynamics of the enzyme on pH 1.5. All calculations were performed by NAMD 2.8 [4] on the m ultimode Linux cluster. For the preparation of the systems\, and analysis of the results VegaZZ 2.4.0 were used [5].\n\nAcknowledgement: The work is supported by the European Commission under EU FP7 project HP-SEE\, http:/ /www.hp-see.eu/. The Ministry of Education and Science of Serbia support this work. Grants 172035 and 172049.\n\nReferences: [1] Mini-Rev. Med. Che m. 7 (2007) 1040\; [2] J. Mol. Biol. 112 (1977) 535\; [3] Proteins 73 (200 8) 765\; [4] J. Compt. Chem. 26 (2005) 1781\; [5] J. Comp. Aided Mol. Des. 18 (2004) 167\n\nhttps://events.saifa.rs/event/291/contributions/192/ LOCATION:National Library of Serbia URL:https://events.saifa.rs/event/291/contributions/192/ END:VEVENT END:VCALENDAR