Effect of Cholesterol on the Properties of Phospholipid Membranes, III. Local Lateral Structure. Abstract: The local lateral structure of dimyristoylphosphatidylcholine (DMPC)-cholesterol mixed membranes of different compositions has been investigated on the basis of computer simulation results. For this purpose, the centers of mass of the molecules of each simulated membrane layer have been projected to the plane of the membrane, and the 2D Voronoi tessellation of the resulting projections has been determined. Various characteristics of the Voronoi polygons (VP) have been determined and compared for cholesterols, their nearest DMPC neighbors, and DMPC molecules having no near cholesterol neighbors. It has been found that there is a strong, specific interaction between cholesterol molecules and their nearest DMPC neighbors, whereas when lacking a sufficient number of cholesterols a different kind of specific interaction occurs between some pairs of neighboring DMPC molecules. These interactions often involve direct cholesterol-DMPC hydrogen bonding and charge pairing between oppositely charged segments of the headgroups of two neighboring DMPCs, respectively. In addition, the DMPC-cholesterol nearest-neighbor interaction involves the ordering effect of the rigid cholesterol ring system on the nearby lipid tails, which helps to keep the hydrocarbon tails and thus the center of mass of the DMPC molecule close to the cholesterol. The analysis of the VP area distributions has revealed that the lateral condensation of the membrane upon adding cholesterol to it can be explained solely by the formation of strongly interacting, often hydrogen-bonded DMPC-cholesterol pairs.