MOLECULAR MODELING

Lennart Nilsson, Professor

THEORETICAL STUDIES OF BIOMOLECULAR INTERACTIONS

Research within the group is focussed on two main lines, with atomic interactions in relation to biological processes as a common theme:
 
  • nucleic acids and their interactions with proteins
  • peptides and their structure and dynamics


    • Theoretical and simulation methods give a very detailed description of biomolecular systems which can serve, not only to fill in the gaps between the experiments, but also to provide predictions and suggestions for further studies. By combining molecular dynamics simulations on a series of related systems with experimental studies of basic physical/chemical properties and structural studies new insights in the underlying mechanisms and processes can be obtained. Since most biomolecular reactions take place in an aqueous environment it is also very important to consider the effects of the surroundings, which may be of several kinds: competition for hydrogen bonds, screening of electrostatic interactions or favoring structural arrangements with minimal exposure of hydrophobic groups, to name but a few possibilities.
    Current projects include studies of stacking-unstacking of nucleotides, binding of the glucocorticoid receptor to DNA, helix forming ability of short peptides in mixed solvents and model building of various proteins.
     

    Lennart.Nilsson@biosci.ki.se

    Lennart Nilsson
    Karolinska Institutet
    Department of Biosciences at NOVUM
    Center for Structural Biochemistry
    S-141 57  HUDDINGE, Sweden
    Phone:          +46 8 608 9228
    Fax:              +46 8 608 9290


    One turn of an alpha-helix used in study of helical stability (Brooks&Nilsson, 1993)

    Openings 

    There are now possibilities for undergraduates to do a diploma thesis project ("exjobb") in the group.

    Group members

    Lennart Nilsson, Professor
    Johan Bredenberg, PhD
    Mikael Gillner, Ph.D.
    Ana Caballero-Herrera, PhD student
    Peter Carlsson, PhD student
    Jianxin Duan, PhD student
    Boel Nyström, PhD student
    Jevgeni Starikow, PhD
    Jan Norberg, Associate professor
    Katarina Lindberg, PhD student
    Sofia Burendahl, PhD student
    Charlotta Hambraeus, PhD

    Recent departures

    Pekka Mark, PhD, TU Munich
    Nicolas Foloppe, Ph.D., Ribotargets, Cambridge, UK
    Mats Eriksson, Ph.D.
    Srikanta Sen, Ph.D., Indian Institute of Chemical Biology, Calcutta
    Ansuman Lahiri, PhD
    Valere Lounnas, Ph.D
    Yun Tang, Ph.D
    Joanna Sarzynska, Ph.D., Institute of Bioorganic Chemistry, Polish Academy of Sciences

    SOME RELEVANT PUBLICATIONS

    Peptides

    De Loof, H., Nilsson, L. & Rigler, R. (1992) Molecular Dynamics Simulation of Galanin in Aqueous and Non-aqueous Solution, J. Am. Chem. Soc., 114, 4028-4035.

    Vogel, H., Nilsson, L., Rigler, R., Meder, S.,Boheim, G., Beck, W., Kurth, H.H. & Jung, G. (1993) Structural Fluctuations Between Two Conformational States of a Transmembrane Helical Peptide Are Related to Its Channel Forming Properties in Planar Lipid Membranes, Eur. J. Bioch. 212, 305-313.

    Whitley, P., Nilsson, L. & von Heijne, G. (1993) A Model for the 3D-Structure of the Membrane Domain of Escherichia coli Leader Peptidase Based on Disulphide Mapping, Biochemistry 32, 8534-8539.

    Brooks, C.L. III & Nilsson, L (1993) The Promotion of Helix Formation in Peptides Dissolved in Alcohol and Water-Alcohol Mixtures, J. Am. Chem. Soc., 115, 11034-11035

    Tyrosine kinase modeling

    Vihinen, M., Vetrie, D., Maniar, H.S., Ochs, H.D., Zhu, Q., Vorechovsky, I., Webster,D., Notarangelo, L.D., Nilsson, L., Sowadski, J.M. & Smith, C.I.E. (1994) Structural Basis for Chromosome X-linked Agammaglobulinemia. A Tyrosine Kinase Disease, Proc. Natl. Acad. Sci. USA 91, 12803-12807.

    Vihinen, M., Nilsson, L. & Smith, C.I.E. (1994) Tec homology (TH) adjacent to the PH domain, FEBS Letters 350, 263-265.

    Vihinen, M., Zvelebil, M.J.J.M., Zhu, Q., Brooimans, R.A., Ochs, H.D., Zegers, B.J.M., Nilsson, L., Waterfield, M.D. & Smith, C.I.E. (1995) Structural Basis for Pleckstrin Homology Domain Mutations in X-linked Agammaglobulinemia, Biochemistry 34, 1475-1481.

    Protein:DNA Interactions

    Elofsson, A., Kulinski, T., Rigler, R. & Nilsson, L. (1993) Site Specific Point Mutation Changes Specificity. A Molecular Modelling Study by Free Energy Simulations and Enzyme Kinetics of the Thermodynamics in Ribonuclease T1 Substrate Interactions, PROTEINS 17, 161-175.

    Zilliacus, J., Wright, A.P.H., Carlstedt-Duke, J., Nilsson, L. & Gustafsson, J.-Å. (1995) Modulation of DNA Binding Specificity Within the Nuclear Receptor Family by Substitutions at a Single Amino Acid Position, PROTEINS 21, 57-67.

    Eriksson, M., Berglund, H., Härd, T. & Nilsson, L. (1993) A Comparison of 15N NMR Relaxation Measurements with a Molecular Dynamics Simulation: Backbone Dynamics of the Glucocorticoid Receptor DNA-binding Domain, PROTEINS, 17, 375-390.

    Eriksson, M.A.L., Härd, T. & Nilsson, L. (1995) Molecular Dynamics Simulations of the DNA -Binding Domain of the Glucocorticoid Receptor as a Dimer in Complex with DNA and as a Monomer in Solution, Biophysical Journal 68, 402-426.

    Eriksson, M.A.L. & Nilsson, L. (1995) Structure, thermodynamics and cooperativity of the glucocorticoid receptor DNA-binding domain in complex with different response elements. Molecular dynamics simulation and free energy perturbation studies, J. Mol. Biol. 253, 453-472.

    Nilsson, L. (1998) Protein Nucleic Acid Interactions. In "Encyclopedia of Computational Chemistry" (Eds. P. von Ragué Schleyer, N.L. Allinger, T. Clark, J. Gasteiger, P.A. Kollman, H. F. Schaefer III) , Vol. 3, 2220-2229, John Wiley & Sons.

    Eriksson, M.A.L. & Nilsson, L. (1999) Structural and Dynamic Differences of the Estrogen Receptor DNA-binding Domain, Binding as a Dimer and as a Monomer to DNA. Molecular Dynamics Simulations Studies, European Biophysics Journal 28, 102-111.

    Tang, Y. & Nilsson, L. (1999) Effect of G40R Mutation on the Binding of Human SRY Protein to DNA: A Molecular Dynamics View, PROTEINS 35, 101-113.

    Tang, Y. & Nilsson, L. (1999) Molecular Dynamics Simulation of the Complex between Human U1A Protein and Hairpin II of U1 snRNAand of the Free RNA in Solution, Biophysical Journal, in press.

    Nucleotides and Nucleic Acids

    Nilsson, L., Åhgren-Stålhandske, A., Sjögren, A.S., Hahne, S. & Sjöberg, B.M. (1990) Three Dimensional Model and Molecular Dynamics Simulation of the Active Site of the Self Splicing Intervening Sequence of the Bacteriophage T4 nrdB Messenger RNA, Biochemistry 29, 10317-10322.

    Norberg, J. & Nilsson, L. (1994) Stacking-Unstacking of the Dinucleoside Monophosphate Guanylyl-3'-5'-Uridine Studied with Molecular Dynamics, Biophysical Journal 67, 812-824.

    Norberg, J. & Nilsson, L. (1995) Stacking Free Energy Profiles for All 16 Natural Ribodinucleoside Monophosphates in Aqueous Solution, J. Am. Chem. Soc., 117,10832-10840.

    Norberg, J. & Nilsson, L. (1995) NMR Relaxation Times, Dynamics and Hydration of a Nucleic Acid Fragment from Molecular Dynamics Simulations, J. Phys. Chem. 99,14876-14884.

    Norberg, J. & Nilsson, L. (1995) Temperature Dependence of the Stacking Propensity of Adenylyl-3',5'-Adenosine, J. Phys. Chem. 99, 3056-3058.

    Norberg, J. & Nilsson, L. (1995) Potential of Mean Force Calculations of the Stacking-Unstacking Process in Single-stranded Deoxyribodinucleoside Monophosphates, Biophysical Journal 69, 2277-2285..

    Sen, S. & Nilsson, L. (1998) Molecular Dynamics of  Duplex Systems Involving PNA: Structural and Dynamical Consequences of the Nucleic Acid Backbone, J. Am. Chem. Soc. 120, 619-631