Area of interest: Polymer-protein interactions

Project Title: Simulation of the interaction of dendritic polymers with bone proteins and inflammation markers
Researchers: Sadra Kashefolgheta (PhD student), Ana Vila Verde (supervisor)
In collaboration with: Prof. Dr. Rainer Haag (FU)

Project description: On-going studies in the Haag group show that dendritic polymers functionalized with anionic groups like phosphate, phosphonate, biphosphonate or sulfate show anti-inflammatory activity and enhanced affinity towards bone. These polymers are hence promising candidates for targeted delivery of bioactive compounds to inflamed sites and bone. For example, the anti-inflammatory properties of dendritic polyglycerol sulfate arise from its inhibition of selectin proteins; its different affinity for hydroxyapatite and collagen - components of bone or cartilage - should allow for targeted drug delivery. The aim of this project is to investigate the molecular scale mechanisms of interaction of anionic dendrimers with selectin or collagen, answering questions such as: How do polyelectrolytes bind to selectin? Why do sulfate-based dendrimers in particular have such high binding affinity for selectin? What is the mechanism of selectin inhibition? Why do polysulfonates have the highest affinity for collagen?  How does the stiffness of the polymeric scaffold and the density of surface functional groups affect binding to target molecules? 

We address these issues using a variety of particle-based simulation methods, with emphasis on classical molecular dynamics. Advanced techniques to enhance sampling of configuration space are systematically used to calculate thermodynamic observables like binding free energies. Ab initio methods are used to parameterize new compounds for classical simulations. The project benefits from frequent discussions with the Haag (FU) and Fratzl (MPIKG) groups, currently investigating this topic using experiments. 

Area of interest: Fluorinated proteins

Project Title: Investigating the role of fluorinated amino acids on protein structure and function using simulation
Researchers: João Robalo (PhD student), Ana Vila Verde (supervisor)
In collaboration with: Prof. Dr. Beate Koksch (FU)

Project description: Proteins containing fluorine atoms are inexistent in nature, but over the past decade many fluorine-substituted protein analogues have been created. We now know that substituting even a single C-H by a C-F group may alter the protein's function, resistance to degradation by proteases or conformational stability with respect to temperature or denaturants. Fluorine substitution is thus a promising tool to enhance the properties of proteins. Presently, we have limited understanding of the molecular scale mechanisms by which fluorination induces particular changes in proteins. This project aims to build this understanding, by using molecular simulations to investigate how fluorinated amino acids differ from natural ones in their interactions with other amino acids, water, or ions. First we will investigate how C-H to C-F mutations alter the intrinsic structural properties of amino acids and those of their water of hydration. In a second stage we will mutate amino acids in small peptides with known structure - e.g. coiled-coils, see Fig. 1 - and will build on what was learned in the first stage to determine the molecular scale origin of differences in the properties of natural and fluorinated peptides. The project will involve frequent discussions with the Koksch group at the FU, benefiting from the group's expertise and on-going work synthesizing and experimentally evaluating fluorinated peptides.

We address these issues using multiple particle-based simulation methods, with emphasis on classical molecular dynamics. Enhanced sampling techniques are systematically used to calculate, e.g., binding free energies and transition rates for rare events. Ab initio methods are used to parameterize new compounds for classical simulations.

Area of interest: Force pathways in proteins

Project Title: Investigating mechanical deformation and force-dependent pathways in proteins using molecular dynamics simulations
Researchers: Chuanfu Luo (post-doc), Ana Bergues Pupo (post-doc), Ana Vila Verde, Reinhard Lipowsky
Supervisors: Ana Vila Verde and Reinhard Lipowsky
In collaboration with: Kerstin Blank (MPIKG)

Project description: Proteins in vivo are often under significant mechanical stress, which affects their conformation and conformational fluctuations. These changes will affect the proteins’ ability to carry out their function, e.g., the enzymatic turnover rate or the stability of a multi-protein complex. At present, however, the molecular mechanisms by which force is transmitted within or between proteins are not understood. Such knowledge is critical to understand how the response of proteins  to mechanical force depends on the intensity, the direction or the application point of the force.  In this project, we will address this general problem by using atomistic molecular dynamics simulations to investigate the effect of mechanical forces on two categories of proteins: enzymes such as lysozymes, and complexes of three proteins such as trimeric coiled coils, see Figure 1. The project will involve learning advanced simulation techniques to enhance sampling of configuration space.

The simulation studies will be pursued in close collaboration with the experimental group of Kerstin Blank at our Max Planck Institute, where atomic force microscopy and single molecule fluorescence experiments will be carried out on the same proteins with the same focus on force-dependent pathways.

Area of interest:  Water and ions

Project Title: Investigating the effect of ions and ion pairs on water structure and dynamics
Researchers: Ana Vila Verde, Reinhard Lipowsky

Project description: Reports from ultrafast pump-probe spectroscopy experiments suggest that densely charged ions such as magnesium and sulfate have a long range effect on water dynamics, cooperatively slowing down water rotation beyond what would be expected from a simple additive model; similar experiments also indicate that even in 1:1 salts, monovalent cations affect the rotational dynamics of the water shell of their counterions. These claims defy evidence from other experiments, which suggest that the effect of anions and cations on water is limited to their first hydration shell and is largely additive. We address this on-going controversy by using classical atomistic molecular dynamics simulations and polarizable models to investigate the dynamics of rotation of water in solutions of salts with high and low charge density.

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