Project

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Multi-scale computer simulations of Biopolymers

English title Multi-scale computer simulations of Biopolymers
Applicant Cascella Michele
Number 139195
Funding scheme SNSF Professorships
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Physical Chemistry
Start/End 01.06.2012 - 31.01.2014
Approved amount 465'830.00
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All Disciplines (3)

Discipline
Physical Chemistry
Biophysics
Biochemistry

Keywords (3)

Computational chemistry; Structural biology; Multiscale simulations

Lay Summary (English)

Lead
Lay summary
Different molecular processes can occur over extremely broad time-scales (from femtosecond to millisecond, seconds and minutes), and may involve very different numbers of atoms. Therefore, in some cases, large system sizes and long time periods place severe restrictions on the nature and type of simulations that can be carried out. In particular, biological systems fall into this category. In the first place, biomolecules such as proteins may contain up to several hundreds of amino acids, i.e., thousands of atoms. Secondly, biological processes may span characteristic time-scales from milliseconds to many minutes, hours or even days. In addition, these processes can occur in solution, and moreover solvent molecules can have an active role and need to be explicitly considered. Finally, dynamical effects both on short and long time scales are extremely important and must be taken into account. Thus, the predictive capability of computational models for biological systems is limited by the overall accuracy to which relevant phase-space regions are sampled. From this standpoint, a direct effort in exploration of novel techniques aimed at improving efficiency of phase-space sampling is needed to successfully develop and apply methods to soft-matter systems.
To bridge the gap between time scales of feasible simulations and those needed for the description of biologically relevant events, coarser description than all-atom Hamiltonians for biopolymers have been proposed. Such schemes are able to efficiently span the phase-space, but they lose the chemical details of a protein sequence. Therefore, they may not be used to investigate all those processes involving molecular recognition. Such processes, however, are usually highly localised, and involve portions of the protein only. Current trends in molecular simulations are driving efforts of different researchers into development of novel multi-scale techniques, able to combine coarse-grained approaches to atomistic details.
In the present proposal, I will complete and extend multiscale methodologies I have been developing in the course of the first years of my work. Such task will be achieved starting from the seeding works as well as ongoing developments achieved in the past years. In particular, I will complete development of a new CG force field for proteins able to reliably span the conformational space, and couple it to hybrid MM/CG methods. Applications to different systems of relevance in biophysics and biochemistry are presented in the second part of the research plan.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Electronic tuning effects via cyano substitution of a fused tetrathiafulvalenebenzothiadiazole dyad for ambipolar transport properties
Amacher A, Luo H, Liu Z, Bircher M, Cascella M, Hauser J, Decurtins S, Zang D, Liu S.-X. (2014), Electronic tuning effects via cyano substitution of a fused tetrathiafulvalenebenzothiadiazole dyad for ambipolar transport properties, in Royal Society of Chemistry Advances, 4, 2873-2878.
Human cellular retinaldehyde binding protein has secondary thermal 9-cis-retinal isomerase activity
Bolze C, Helbling R, Owen R, Pearson A, Pompidor G, Dworkowski F, Fuchs M, Furrer J, Golczak M, Palczewski K, Cascella M, Stocker A (2014), Human cellular retinaldehyde binding protein has secondary thermal 9-cis-retinal isomerase activity, in Journal of the American Chemical Society, 136, 137-146.
Mechanisms of Ligand–Protein Interaction in Sec-14-like Transporters Investigated by Computer Simulations
Helbling Rachel, Lamprakis Christos, Aeschimann Walter, Bolze Christin, Stocker Achim, Cascella Michele (2014), Mechanisms of Ligand–Protein Interaction in Sec-14-like Transporters Investigated by Computer Simulations, in Chimia, 68(9), 615-619.
Cellular Retinaldehyde Binding Protein – Different binding modes and micro-solvation patterns for high-affinity 9-cis and 11-cis-retinal substrates
Helbling R, Bolze C, Golczak M, Palczewski K, Stocker A, Cascella M (2013), Cellular Retinaldehyde Binding Protein – Different binding modes and micro-solvation patterns for high-affinity 9-cis and 11-cis-retinal substrates, in Journal of Physical Chemistry B, 117, 10719-10729.
Cis-carotenoids and the chemistry of vision
Cascella Michele, Baerfuss Simon, Stocker Achim (2013), Cis-carotenoids and the chemistry of vision, in Archives of Biochemistry and Biophysics, 539, 187-195.
Electrostatics and Flexibility Drive Membrane Recognition and Early Penetration by Antimicrobial Peptide Dendrimer bH1
Ravi H, Stach M, Soares T, Darbre T, Reymond J-L, Cascella M (2013), Electrostatics and Flexibility Drive Membrane Recognition and Early Penetration by Antimicrobial Peptide Dendrimer bH1, in Chemical Communications, 49, 8821-8823.
Multidrug resistance and efflux pumps: insights from molecular dynamics simulations
Collu Francesca, Cascella Michele (2013), Multidrug resistance and efflux pumps: insights from molecular dynamics simulations, in Current Topics in Medicinal Chemistry, 13, 3165-3183.
On the acceleration of Cu electrodeposition by TBPS (3,3-thiobis-1-propanesulfonic acid): A combined electrochemical, STM, NMR, ESI-MS and DFT study
Hai N, Furrer J, Gjuroski I, Bircher M, Cascella M, Broekmann P (2013), On the acceleration of Cu electrodeposition by TBPS (3,3-thiobis-1-propanesulfonic acid): A combined electrochemical, STM, NMR, ESI-MS and DFT study, in Journal of the Electrochemical Society, 160, D3158-D3164.
Supramolecular organization of heptapyrenotide oligomers – an in depth investigation by molecular dynamics simulations
Simona Fabio, Nussbaumer Alina, Haener Robert, Cascella Michele (2013), Supramolecular organization of heptapyrenotide oligomers – an in depth investigation by molecular dynamics simulations, in Journal of Physical Chemistry B, 117, 2576.
Engineering tocopherol selectivity in alpha-TTP - a combined in vitro/in silico study
Helbling Rachel E., Aeschimann Walter, Simona Fabio, Stocker Achim, Cascella Michele (2012), Engineering tocopherol selectivity in alpha-TTP - a combined in vitro/in silico study, in PLoS ONE, 7, e49195.
Excited state properties of formamide in water solution: an ab-initio study
Garbuio Viviana, Cascella Michele, Del Sole Rodolfo, Pulci Olivia (2012), Excited state properties of formamide in water solution: an ab-initio study, in Journal of Chemical Physics, 137, 164317.
Recognition of Imipenem and Meropenem by RND-transporter MexB studied by computer simulations
Collu Francesca, Vargiu Attilio V., Dreier Juerg, Cascella Michele, Ruggerone Paolo (2012), Recognition of Imipenem and Meropenem by RND-transporter MexB studied by computer simulations, in Journal of the American Chemical Society, 134, 19146.
Electrostatic-consistent coarse-grained potentials for molecular simulations of proteins
Spiga Enrico, Alemani Davide, Degiacomi Matteo, Cascella Michele, Dal Peraro Matteo, Electrostatic-consistent coarse-grained potentials for molecular simulations of proteins, in Journal of Chemical Theory and Computation, --.

Collaboration

Group / person Country
Types of collaboration
University of Cagliari Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Case Western Reserve University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Basilea Pharmaceutica International Ltd. Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Fribourg Chemical Society Individual talk Multidrug resistance in P. aeruginosa: supporting the fight with computer simulations 19.11.2013 Fribourg, Switzerland Cascella Michele;
CECAM workshop: “Innovative approaches to computational drug discovery" Talk given at a conference Micro-solvation properties drive ligand binding and translocation in RND multidrug efflux pump MexB from Pseudomonas aeruginosa 01.10.2013 Lausanne, Switzerland Cascella Michele;
53rd Sanibel Symposium Talk given at a conference Combined classical MD, hybrid QM/MM simulations and in vitro tests reveal a novel function for retinal transporter protein CRALBP 17.02.2013 St. Simons Island, GA, USA, United States of America Cascella Michele;
10th World Congress of Computational Mechanics Talk given at a conference Modeling mechanical properties of biological polymers by atomistic and multiscale simulations 08.07.2012 Sao Paulo, Brazil, Brazil Cascella Michele;


Associated projects

Number Title Start Funding scheme
118930 Multi-scale computer simulations of Biopolymers 01.06.2008 SNSF Professorships

Abstract

Different molecular processes can occur over extremely broad time-scales (from 10-12 to 102 s), and may involve very different numbers of atoms. Therefore, in some cases, large system sizes and long time periods place severe restrictions on the nature and type of simulations that can be carried out. In particular, biological systems fall into this category. In the first place, biomolecules such as proteins may contain up to several hundreds of amino acids, i.e., thousands of atoms. Secondly, biological processes may span characteristic time-scales from milliseconds to many minutes, hours or even days. In addition, these processes can occur in solution, and moreover solvent molecules can have an active role and need to be explicitly considered. Finally, dynamical effects both on short and long time scales are extremely important and must be taken into account. Thus, the predictive capability of computational models for biological systems is limited by the overall accuracy to which relevant phase-space regions are sampled. From this standpoint, a direct effort in exploration of novel techniques aimed at improving efficiency of phase-space sampling is needed to successfully develop and apply methods to soft-matter systems. To bridge the gap between time scales of feasible simulations and those needed for the description of biologically relevant events, coarser description than all-atom Hamiltonians for biopolymers have been proposed. Such schemes are able to efficiently span the phase-space, but they lose the chemical details of a protein sequence. Therefore, they may not be used to investigate all those processes involving molecular recognition. Such processes, however, are usually highly localised, and involve portions of the protein only. Current trends in molecular simulations are driving efforts of different researchers into development of novel multi-scale techniques, able to combine coarse-grained approaches to atomistic details.In the present proposal, I will complete and extend multiscale methodologies I have been developing in the course of the first years of my work. Such task will be achieved starting from the seeding works as well as ongoing developments achieved in the past years. In particular, I will complete development of a new CG force field for proteins able to reliably span the conformational space, and couple it to hybrid MM/CG methods. Applications to different systems of relevance in biophysics and biochemistry are presented in the second part of the research plan.
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