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Multi-scale computer simulations of Biopolymers

English title Multi-scale computer simulations of Biopolymers
Applicant Cascella Michele
Number 118930
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 01.06.2008 - 31.05.2012
Approved amount 1'528'739.00
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All Disciplines (3)

Physical Chemistry

Keywords (10)

Molecular Dynamics; Coarse Grained models; Biopolymers; Computational Biophysics; Protein-Ligand interactions; Density Functional Theory; Multiscale modeling; coarse-grained; computational biophysiscs; DFT

Lay Summary (English)

Lay summary
Different molecular processes occur over extremely broad time-scales (from fs to hours), 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 computer simulations that can be carried out. In particular, biological systems fall into this category. Firstly, biomolecules may contain up to thousands of atoms. Secondly, biological processes may span characteristic time-scales from milliseconds to even days. In addition, these processes occur in solution, where 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. 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 project, I plan to develop of a hybrid molecular mechanics / coarse-grained method, where a portion of the molecular system (i.e. a protein binding site) is treated at all-atom level, and the rest is trated at coarse-grained level. Applications to different systems of relevance in biophysics and biochemistry will be developed in parallel with the method. In particular, I will work on protein-DNA interactions, mechanisms of viral infection, allosteric phenomena, and structure-to-function relationship in multi-copper oxidases. The results achieved in the project will have a potential impact both on basic understanding of biomolecular phenomena and on biotechnological and pharmaceutical applications.In particular, the proposed applications will contribute to the development of bioengineered molecules useful in soil bioremediation, will shed light on the molecular origin of allosteric effects, which are fundamental in bio-factor expression and regulation, and will contribute to the understanding of the molecular mechanisms that regulate two major problems in medical sciences: viral infection and natural tumor suppression.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants



Molecular origin of piezo- and pyro-electric properties of collagen investigated by molecular dynamics simulations
Ravi H.K. Simona F. Hulliger J. Cascella M. (2012), Molecular origin of piezo- and pyro-electric properties of collagen investigated by molecular dynamics simulations, in Journal of Physical Chemistry B, 116, 1901-1907.
From Structure to Function: Caracterisation of Cu(I) adducts in Leveler Additives by DFT Calculations
Simona F. Hai N. T. M. Broekmann P. Cascella M. (2011), From Structure to Function: Caracterisation of Cu(I) adducts in Leveler Additives by DFT Calculations, in Journal of Physical Chemistry Letters, 2, 3081-3084.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
CPMD meeting 03.09.2011 Barcelona

Associated projects

Number Title Start Funding scheme
139195 Multi-scale computer simulations of Biopolymers 01.06.2012 SNSF Professorships


Over the last few decades, a wide range of disciplines, from molecularbiology to materials sciences, have started to overlap in a commongeneral framework called "the nanosciences". The reason for thisconvergence is that events occurring at the nanometre length-scale,i.e. atomic- and molecular-level interactions, drive the processes ofdifferent systems at the macroscopic level. Therefore, condensedmatter theory and techniques derived from it can nowadays be extremelyhelpful for the basic understanding of a broad series of phenomena ofvarious interests and applications, i.e., from development ofelectronic devices to drug design. Among the various sciences thatinvestigate the nanoscale world, computational-based studies offer thepossibility to investigate the behaviour of matter directly at theatomistic level, under highly controlled conditions.Current computational power limits all-atom molecular dynamicssimulations (MM) to time-scales of ~10-100 ns for systems as large asan order of 10.000-100.000 atoms. These time/size bottlenecks are toostrict to efficiently explore the phase space of relevant biologicalprocesses involving bio-polymers (e.g., lipid self-assembly,ligand-protein recognition, signalling, protein-protein andprotein-DNA interactions). In fact, biopolymers may contain up toseveral hundreds of units, and phenomena in which they are involved canspan characteristic timescales that go up to milliseconds, seconds,and even to minutes or days. Moreover, biological polymers are found insolution, and solvent molecules can have an active role in manyprocesses, therefore, they have to be taken into account. Thus, thepredictive capability of computational models for biological systemsis limited by the overall accuracy to which relevant phase-spaceregions can be sampled. From this standpoint, a direct effort in theexploration of novel techniques aimed at improving the efficiency ofphase-space sampling is needed. To bridge the gap between time scales of feasible simulations andthose needed for the description of biologically relevant events,coarser models than all-atom parameterised Hamiltonians have beenproposed. Typically, coarse-grained models of proteins (CG) reduce thedescription of each residue to one or two centroids. Unfortunately,such schemes lose the chemical details of the systems.Therefore, they may not be used to investigate all those processesinvolving molecular recognition. Such processes, however, are usuallyhighly localised, and involve small portions of the protein. In thespirit of hybrid QM/MM methods developed by the quantum-chemistrycommunity, a recent work [M. Neri et al, PRL 95, 218102 (2005)] showedthat a hybrid all-atom/coarse-grained (MM/CG) description forproteins is straightforward to implement. The great advantage ofcombining all-atom approaches with coarse-grained Hamiltonians liesin the possibility to exploit longer simulation times while retainingthe detail in the regions of chemical interest. The researchproposal presented here is centered around two main interests. The first interest will be in focusing efforts for a further development of the MM/CG Hamiltonian. In particular, effortswill be spent for introducing fast and efficient schemes aimed atreproducing the electrostatic coupling between the MM and the CGparts; developing efficient routines to overcome the problem of the solventdiffusion at the MM boundaries; and finally, implementing novel force-fieldbased CG Hamiltonians, in order to reduce the strong bias toward theexperimental X-ray structure produced by topological-basedCG-Hamiltionians. The study of systems of major relevance inbiochemistry and biophysics will constitute the second area of interest of theproposed research. In particular, I will focus on the study of theredox properties of laccase, the study of the mechanical propertiesand allosteric phenomena in actin filaments, the study of themechanisms of membrane fusion in viral infections, and the studyof protein-DNA interactions in the p53 tumour suppressor factor. Suchprojects will make use of standard MM, QM/MM and CG methods alreadyavailable in the field, in addition to the MM/CG techniques that willbe developed in parallel. All proposed application projects havepotential high impact on both basic understanding of biomolecularprocesses and on possible future biotechnological and pharmaceuticaldevelopments.