Understanding complex bio-molecular events via the orthogonal space sampling scheme

A generalized ensemble based enhanced sampling scheme, the Orthogonal Space Sampling (OSS) approach, is introduced in this thesis. Due to the fact that the OSS scheme simultaneously accelerates the motions of a target event and its coupled environment relaxation, this scheme can dramatically enhanced the sampling efficiency of complex bio-molecular events. The OSS scheme is formulized and applied in three different scenarios.;In the first study, the geometry based OSS free energy calculation algorithm was used study the localization and orientation behaviors of small molecules during trans-membrane permeation. The free energy profiles for the trans-membrane permeation of a typical set of small molecules are quantitatively predicted in 100ns time-scale. The coexistence of the polar and nonpolar groups is the structural determinant for the interfacial region localization effect. The interaction strength between the polar analog and the lipid head group is responsible for the orientation behaviors of a small molecule.;In the second study, two small model systems, alanine dipeptide and aspartate-arginine dipeptide, and two large protein systems including bovine pancreatic trypsin inhibitor (BPTI) and Adenylate kinase (ADK) in explicit solvent are investigated via the OSS enhanced sampling scheme. Efficient state transitions in the two dimensional essential energy space lead to fast conformational changes of all the systems and the classical micro-second to milli-second time-scale motions of BPTI and ADK can be achieved within nano-second time-scale.;Finally, the OSS alchemical free energy calculation scheme is utilized to study the mechanism of an important process, pseudouridylation. The results from both experimental and computational studies clearly support the Michael mechanism in which C6 is the target carbon atom for the initial nucleophilic attack in pseudouridylation.;In sum, the OSS scheme is a robust enhanced sampling approach for both free energy calculation and ab initio prediction of large scale protein conformational changes. Typical micro-second to milli-second time scale complex bio-molecular events can be achieved within nano-second time scale under the current scheme. Other complex systems are expected to be investigated in future studies using this method.