Conformational dynamics, flexibility and recognition in biological macromolecules - Lennart Nilsson

We investigate interactions between proteins and nucleic acids using computer simulations.

Most cellular functions, and thus the survival of the cell, are critically dependent on the ability of the many components of the cell to interact properly and in a controlled fashion, forming more or less stable complexes that may involve dozens of protein and nucleic acid components. Some of these complexes are high-affinity, but in many cases they are transient, and the binding reactions, as well as conformational rearrangements of individual components, which may be partially disordered, exhibit complex kinetics. The focus of our studies is the kinetics of such conformational distributions in nucleic acids and proteins.

Illustration of DNA spirals in red, blue and green with close-ups of Cytosine
Snapshots from simulation of DNA triple helix, showing stabilising effect of protonation on Cytosine in the third strand. Left: Standard Cytosine. Right: Protonated Cytosine. Illustration: Lennart Nilsson’s group

We use computational methods, mainly molecular dynamics (MD) simulation, to shed light on the balance between different interactions that stabilise the structural elements as well as the complexes, and to understand how small sequence changes or changes in the environment can modulate function, by affecting structural and dynamic properties. In the last decade computer hardware has evolved to a point where it is possible to perform meaningful studies of flexible and partially disordered biomolecules, and go beyond analyses of the native state(s) to collect data on structural distributions. In parallel with this development, theoretical advances have been made that allow us to compute quantitative descriptions of the kinetics of transitions between intermediates and other (meta)stable states in such distributions using so-called Markov-State-Models (MSMs).

The purpose of these investigations is to provide insight in atomistic detail into the role of structural flexibility and kinetics in proteins and DNA/RNA in relation to their biological function, and to suggest methods to affect pathological states using small molecules.

Group members

Selected Publications

Two distinct DNA sequences recognized by transcription factors represent enthalpy and entropy optima
Morgunova, Ekaterina, Yimeng Yin, Pratyush K. Das, Arttu Jolma, Fangjie Zhu, Alexander Popov, You Xu, Lennart Nilsson, and Jussi Taipale. 2018. eLife, 7: e32963.

LNA effects on DNA binding and conformation: from single strand to duplex and triplex structures
Pabon-Martinez, Y. Vladimir, You Xu, Alessandra Villa, Karin E. Lundin, Sylvain Geny, Chi-Hung Nguyen, Erik B. Pedersen, Per T. Jørgensen, Jesper Wengel, Lennart Nilsson, C. I. Edvard Smith, and Rula Zain. 2017. Scientific Reports, 7: 11043.

A subset of functional adaptation mutations alter propensity for α-helical conformation in the intrinsically disordered glucocorticoid receptor tau1core activation domain
Salamanova, Evdokiya, Joana Costeira-Paulo, Kyou-Hoon Han, Do-Hyoung Kim, Lennart Nilsson, and Anthony P. H. Wright. 2018. Biochimica et Biophysica Acta (BBA) - General Subjects, 1862: 1452-61.

Additive CHARMM force field for naturally occurring modified ribonucleotides
Xu, You, Kenno Vanommeslaeghe, Alexey Aleksandrov, Alexander D. MacKerell, and Lennart Nilsson. 2016. Journal of Computational Chemistry, 37: 896-912.