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. 2021 Mar 11;22(6):2842.
doi: 10.3390/ijms22062842.

Microscopic Interactions of Melatonin, Serotonin and Tryptophan with Zwitterionic Phospholipid Membranes

Jordi Martí  1 , Huixia Lu  2
Affiliations

Microscopic Interactions of Melatonin, Serotonin and Tryptophan with Zwitterionic Phospholipid Membranes

Jordi Martí et al. Int J Mol Sci. .

Abstract

The interactions at the atomic level between small molecules and the main components of cellular plasma membranes are crucial for elucidating the mechanisms allowing for the entrance of such small species inside the cell. We have performed molecular dynamics and metadynamics simulations of tryptophan, serotonin, and melatonin at the interface of zwitterionic phospholipid bilayers. In this work, we will review recent computer simulation developments and report microscopic properties, such as the area per lipid and thickness of the membranes, atomic radial distribution functions, angular orientations, and free energy landscapes of small molecule binding to the membrane. Cholesterol affects the behaviour of the small molecules, which are mainly buried in the interfacial regions. We have observed a competition between the binding of small molecules to phospholipids and cholesterol through lipidic hydrogen-bonds. Free energy barriers that are associated to translational and orientational changes of melatonin have been found to be between 10-20 kJ/mol for distances of 1 nm between melatonin and the center of the membrane. Corresponding barriers for tryptophan and serotonin that are obtained from reversible work methods are of the order of 10 kJ/mol and reveal strong hydrogen bonding between such species and specific phospholipid sites. The diffusion of tryptophan and melatonin is of the order of 10-7 cm2/s for the cholesterol-free and cholesterol-rich setups.

Keywords: melatonin; phospholipid membrane; serotonin; tryptophan.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure A1
Figure A1
Convergence of MD simulations through RDF profiles as a function of simulation time for the production run of TRP in the DPPC and CHOL model membrane.
Figure A2
Figure A2
Time cumulative free energy profiles at the 30% cholesterol system. Bottom: CV1, top: CV2.
Figure 1
Figure 1
Atomic structures of melatonin, serotonin, tryptophan, dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC), and cholesterol. Backbone hydrogens are not explicitly shown. The highlighted labels will be referred in the text.
Figure 2
Figure 2
Area per lipid of systems with different cholesterol contents: 0%, 30%, and 50% as a function of simulation time.
Figure 3
Figure 3
Z-axis location of the center of mass of MEL in a DMPC lipid membrane with different cholesterol contents as a function of simulation time. The green dashed line indicates the geometrical center of the bilayer membrane. Data partially taken from Ref. [108]. (a) 0% cholesterol, (b) 30% cholesterol and (c) 50% cholesterol. Red diamonds indicate the position of MEL and blue circles indicate the position of phosphorous atoms of DMPC lipids.
Figure 4
Figure 4
Radial distribution functions for TRP with DPPC (charged sites ‘H1’, ‘H2’, ‘O2’, and ‘O8’, see Figure 1): H1TRP-O2 (top left), H1TRP-O8 (bottom left), H2TRP-O2 (top right), and H2TRP-O8 (bottom right). Data are partially taken from Ref. [107].
Figure 5
Figure 5
Selected radial distribution functions for hydrogens of MEL (‘H15’ and ‘H16’) with DMPC (‘O2’ (representing ‘O1&O2’) and ‘O6’ (representing ‘O6’ and ‘O8’). The labels as in Figure 1. Data are partially taken from Ref. [108].
Figure 6
Figure 6
Two principal configurations of MEL: folded (left) and extended (right), indicated by the dihedral (torsional) angle Ψ. The atoms forming the melatonin molecule are: carbon (cyan), oxygen (red), hydrogen (white), and nitrogen (blue).
Figure 7
Figure 7
Angular distributions for the selected dihedral angle Ψ as a function of simulation time. Percentages of cholesterol are: 0% (black circles), 30% (red squares), and 50% (green triangles). The dashed lines indicate average values and are a guide for the eye.
Figure 8
Figure 8
Reversible work W(r) (in kBT) for DPPC-small molecules: TRP, SER and MEL. In the present system 1 kBT∼2.7 kJ/mol. Hydrogen and oxygens of DPPC are indicated with same labels, as described in Figure 1. Data are partially taken from Ref. [98].
Figure 9
Figure 9
Two-dimensional (2D) free energy landscapes F(Ψ,z) (in kJ/mol) in the cholesterol-free case. Four stable state basins (A,B,C,D) are indicated.
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